Nanofilm compositions with polymeric components

ABSTRACT

Nanofilms useful for filtration are prepared from amphiphilic species and one or more polymeric components. The amphiphilic species or components may be oriented on an interface or surface. A nanofilm may be prepared by coupling one or more of the components. The nanofilm may also be deposited or attached to a substrate.

CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional ApplicationSerial No. 60/411,588, filed Sep. 17, 2002, herein incorporated byreference in its entirety.

TECHNICAL FIELD

[0002] This invention relates to thin layer compositions which arenanofilms prepared from various macrocyclic module components andvarious polymeric and amphiphilic components. This invention alsorelates to the fields of organic chemistry and nanotechnology, inparticular, it relates to nanofilm compositions useful for filtration.

BACKGROUND OF THE INVENTION

[0003] Nanotechnology involves the ability to engineer novel structuresat the atomic and molecular level. One area of nanotechnology is todevelop chemical building blocks from which hierarchical molecules ofpredicted properties can be assembled. An approach to making chemicalbuilding blocks or nanostructures begins at the atomic and molecularlevel by designing and synthesizing starting materials with highlytailored properties. Precise control at the atomic level is thefoundation for development of rationally tailoredsynthesis-structure-property relationships which can provide materialsof unique structure and predictable properties. This approach tonanotechnology is inspired by nature. For example, biologicalorganization is based on a hierarchy of structural levels: atoms formedinto biological molecules which are arranged into organelles, cells, andultimately, into organisms. These building block capabilities areunparalleled by conventional materials and methods such aspolymerizations which produce statistical mixtures or confinement ofreactants to enhance certain reaction pathways. For example, from twentycommon amino acids found in natural proteins, more than 105 stable andunique proteins are made.

[0004] One field that will benefit from nanotechnology is filtrationusing membranes. Conventional membranes used in a variety of separationprocesses can be made selectively permeable to various molecularspecies. The permeation properties of conventional membranes generallydepend on the pathways of transport of species through the membranestructure. For example, while the diffusion pathway in conventionalselectively permeable materials can be made tortuous in order to controlpermeation, porosity is not well defined or controlled by conventionalmethods. The ability to fabricate regular or unique pore structures ofmembranes is a long-standing goal of separation technology.

[0005] Resistance to flow of species through a membrane may also begoverned by the flow path length. Resistance can be greatly reduced byusing a very thin film as a membrane, at the cost of reduced mechanicalstrength of the membrane material. Conventional membranes may have abarrier thickness of at least one to two hundred nanometers, and oftenup to millimeter thickness. In general, a thin film of membrane barriermaterial can be deposited on a porous substrate of greater thickness torestore material strength.

[0006] Membrane separation processes are used to separate componentsfrom a fluid in which atomic or molecular components having sizessmaller than a certain “cut-off” size can be separated from componentsof larger size. Normally, species smaller than the cut-off size arepassed by the membrane. The cut-off size may be an approximate empiricalvalue which reflects the phenomenon that the rate of transport ofcomponents smaller than the cut-off size is merely faster than the rateof transport of larger components. In conventional pressure-drivenmembrane separation processes, the primary factors affecting separationof components are size, charge, and diffusivity of the components in themembrane structure. In dialysis, the driving force for separation is aconcentration gradient, while in electrodialysis electromotive force isapplied to ion selective membranes.

[0007] In all these methods what is required is a selectively permeablemembrane barrier to components of the fluid to be separated.

SUMMARY OF THE INVENTION

[0008] In one aspect, the invention provides nanofilm compositions. Insome embodiments, the nanofilm composition comprises a reaction productof macrocyclic modules and at least one polymeric component. In someembodiments, the nanofilm composition comprises a reaction product of apolymeric component and an amphiphile. In other embodiments, thenanofilm composition comprises a reaction product of a polymericcomponent, wherein the polymeric components are linked by linkermolecules. In still other embodiments, the nanofilm compositioncomprises a reaction product of at least two polymeric components,wherein the first polymeric component is a polymerizable amphiphile, andthe second polymeric component is a polymerizable monomer.

[0009] In some embodiments, the macrocyclic modules are selected fromthe group consisting of Hexamer 1a, Hexamer 1dh, Hexamer 3j-amine,Hexamer 1jh, Hexamer 1jh-AC, Hexamer 2j-amine/ester, Hexamer 1dh-acryl,Octamer 5j-haspartic, Octamer 4jh-acryl, and mixtures thereof In somepreferred embodiments, the macrocyclic modules are Hexamer 1dh.

[0010] In some embodiments, the polymeric component comprises apolymerizable monomer. In some embodiments, the polymerizable monomercomprises CH₂═CHC(O)OCH₂CH₂OH. In other embodiments, the polymericcomponent comprises a polymerizable amphiphile. In some embodiments, thepolymerizable amphiphile is selected from the group consisting ofamphiphilic acrylates, amphiphilic acrylamides, amphiphilic vinylesters, amphiphilic anilines, amphiphilic diynes, amphiphilic dienes,amphiphilic acrylic acids, amphiphilic enes, amphiphilic cinnamic acids,amphiphilic amino-esters, amphiphilic oxiranes, amphiphilic amines,amphiphilic diesters, amphiphilic diacids, amphiphilic diols,amphiphilic polyols, and amphiphilic diepoxides. In some embodiments,the polymeric component is a polymer. In some embodiments, the polymericcomponent is amphiphilic.

[0011] In some embodiments, the polymeric component is selected from thegroup consisting of poly(maleic anhydride)s, poly(ethylene-co-maleicanhydride)s, poly(maleic anhydride-co-alpha olefin)s, polyacrylates,polymethylmethacrylate, polymers containing at least one oxacyclopropanegroup, polyethyleneimides, polyetherimides, polyethylene oxides,polypropylene oxides, polyurethanes, polystyrenes, poly(vinyl acetate)s,polytetrafluoroethylenes, polyethylenes, polypropylenes,ethylene-propylene copolymers, polyisoprenes, polyneopropenes,polyamides, polyimides, polysulfones, polyethersulfones, polyethyleneterephthalates, polybutylene terephthalates, polysulfonamides,polysulfoxides, polyglycolic acids, polyacrylamides, polyvinylalcohols,polyesters, polyester ionomers, polycarbonates, polyvinylchlorides,polyvinylidene chlorides, polyvinylidene fluorides,polyvinylpyrrolidones, polylactic acids, polypeptides, polysorbates,polylysines, hydrogels, carbohydrates, polysaccharides, agaroses,amyloses, amylopectins, glycogens, dextrans, celluloses, celluloseacetates, chitins, chitosans, peptidoglycans, glycosaminoglycans,polynucleotides, poly(T), poly(A), nucleic acids, proteoglycans,glycoproteins, glycolipids, and mixtures thereof. In some preferredembodiments, the polymeric component is poly(maleic anhydride-co-alphaolefin).

[0012] In some embodiments, the amphiphile is a polymerizableamphiphile. In some embodiments, the polymerizable amphiphile isselected from the group consisting of amphiphilic acrylates, amphiphilicacrylamides, amphiphilic vinyl esters, amphiphilic anilines, amphiphilicdiynes, amphiphilic dienes, amphiphilic acrylic acids, amphiphilic enes,amphiphilic cinnamic acids, amphiphilic amino-esters, amphiphilicoxiranes, amphiphilic amines, amphiphilic diesters, amphiphilic diacids,amphiphilic diols, amphiphilic polyols, and amphiphilic diepoxides. Insome embodiments, the amphiphile is non-polymerizable. In someembodiments, the non-polymerizable amphiphile is selected from the groupconsisting of decylamine and stearic acid.

[0013] In some embodiments, the nanofilm composition may furthercomprise a non-polymerizable amphiphile. In some embodiments, thenon-polymerizable amphiphile is selected from the group consisting ofdecylamine and stearic acid. In some embodiments, the polymericcomponent is a polymer, and the non-polymerizable amphiphiles arecoupled to the polymer.

[0014] In some embodiments, the macrocyclic modules are coupled to eachother. In some embodiments, the macrocyclic modules are coupled to theat least one polymeric component. In some embodiments, the polymericcomponents are coupled to each other. In some embodiments, the at leastone polymeric component is coupled to an amphiphile. In someembodiments, the coupling is through linker molecules. In someembodiments, the linker molecules are selected from the group consistingof

[0015] and mixtures thereof; wherein m is 1-10, n is 1-6, R is —H or—CH₃, R′ is —(CH₂)_(n)— or phenyl, R″ is —(CH₂)_(n)—, polyethyleneglycol (PEG), or polypropylene glycol (PPG), and X is Br, Cl, I, orother leaving group.

[0016] In some embodiments, the nanofilm composition is prepared by aprocess comprising polymerizing the at least one polymeric component atan air-water interface. In some embodiments, the nanofilm composition isprepared by a process comprising polymerizing polymerizable amphiphilesat an air-water interface.

[0017] In some embodiments, the area fraction of the polymericcomponents is from 0.5 to 98 percent. In other embodiments, the areafraction of the polymeric components is less than about 20 percent. Inyet other embodiments, the area fraction of the polymeric components isless than about 5 percent.

[0018] In some embodiments, the thickness of the nanofilm composition isless than about 30 nanometers. In other embodiments, the thickness ofthe nanofilm composition is less than about 6 nanometers. In yet otherembodiments, the thickness of the nanofilm composition is less thanabout 2 nanometers.

[0019] In some embodiments, the nanofilm composition comprises at leasttwo layers of a nanofilm. In some embodiments, the nanofilm compositionfurther comprises at least one spacing layer between any two of thenanofilm layers. In some embodiments, the spacing layer comprises alayer of a polymer, a gel, or inorganic particles.

[0020] In some embodiments, the nanofilm composition is deposited on asubstrate. In some embodiments, the nanofilm is coupled to the substratethrough the polymeric component. In some embodiments, the substrate isporous. In other embodiments, the substrate is non-porous. In otherembodiments, the nanofilm is coupled to the substrate throughbiotin-strepavidin mediated interaction.

[0021] In some embodiments, the surface loss modulus of the nanofilmcomposition at a surface pressure from 5-30 mN/m is less than about 50%of the surface loss modulus of the same nanofilm composition madewithout the polymeric components. In other embodiments, the surface lossmodulus of the nanofilm composition at a surface pressure from 5-30 mN/mis less than about 30% of the surface loss modulus of the same nanofilmcomposition made without the polymeric components. In yet otherembodiments, the surface loss modulus of the nanofilm composition at asurface pressure from 5-30 mN/m is less than about 20% of the surfaceloss modulus of the same nanofilm composition made without the polymericcomponents.

[0022] The nanofilm compositions may have a filtration function whichmay be used to describe the species that pass through the nanofilmcompositions. A nanofilm composition may be permeable only to aparticular species, including anions, cations, and neutral solutes in aparticular fluid, and species smaller than the particular species. Aparticular nanofllm composition may have high permeability for a certainspecies in a certain solvent. A nanofilm composition may have lowpermeability for certain species in a certain solvent. A nanofilmcomposition may have high permeability for certain species and lowpermeability for other species in a certain solvent. In one embodiment,a nanofilm composition may have the following filtration function:MOLECULAR SOLUTE WEIGHT PASS/NO PASS Albumin 68 kDa NP Ovalbumin 44 kDaP Myoglobin 17 kDa P β₂-Microglobulin 12 kDa P Insulin 5.2 kDa P VitaminB₁₂ 1350 Da P Urea, H₂O, ions <1000 Da P

[0023] In another embodiment, a nanofilm composition may have thefollowing filtration function: MOLECULAR SOLUTE WEIGHT PASS/NO PASSβ₂-Microglobulin 12 kDa NP Insulin 5.2 kDa NP Vitamin B₁₂ 1350 Da NPGlucose 180 Da NP Creatinine 131 Da NP H₂PO₄ ⁻, HPO₄ ²⁻ ≈97 Da NP HCO₃ ⁻61 Da NP Urea 60 Da NP K+ 39 Da P Na+ 23 Da P

[0024] In another embodiment, the nanofilm composition is impermeable toviruses and larger species. In other embodiments, the nanofilmcomposition is impermeable to immunoglobulin G and larger species. Inother embodiments, the nanofilm composition is impermeable to albuminand larger species. In other embodiments, the nanofilm composition isimpermeable to β₂-Microglobulin and larger species. In otherembodiments, the nanofilm composition is permeable only to water andsmaller species. In another embodiment, the nanofilm composition haspermeability for water molecules and Na⁺, K⁺, and Cs⁺ in water. Inanother embodiment, the nanofilm composition has low permeability forglucose and urea. In another embodiment, the nanofilm composition hashigh permeability for water molecules and Cl⁻ in water. In anotherembodiment, the nanofilm composition has high permeability for watermolecules and K⁺ in water, and low permeability for Na⁺ in water. Inanother embodiment, the nanofilm composition has high permeability forwater molecules and Na⁺ in water, and low permeability for K⁺ in water.In another embodiment, the nanofilm composition has low permeability forurea, creatinine, Li⁺, Ca²⁺, and Mg²⁺ in water. In another embodiment,the nanofilm composition has high permeability for Na⁺, K⁺, hydrogenphosphate, and dihydrogen phosphate in water. In another embodiment, thenanofilm composition has high permeability for Na⁺, K⁺, and glucose inwater. In another embodiment, the nanofilm composition has lowpermeability for myoglobin, ovalbumin, and albumin in water. In anotherembodiment, the nanofilm composition has high permeability for organiccompounds and low permeability for water. In another embodiment, thenanofilm composition has low permeability for organic compounds and highpermeability for water. In another embodiment, the nanofilm compositionhas low permeability for water molecules and high permeability forhelium and hydrogen gases.

[0025] A nanofilm composition may have a molecular weight cut off. Inone embodiment, the nanofilm composition has a molecular weight cut-offof about 13 kDa. In another embodiment, the nanofilm composition has amolecular weight cut-off of about 190 Da. In another embodiment, thenanofilm composition has a molecular weight cut-off of about 100 Da. Inyet another embodiment, the nanofilm composition has a molecular weightcut-off of about 45 Da. In another embodiment, the nanofilm compositionhas a molecular weight cut-off of about 20 Da.

[0026] In another aspect the invention provides compositions comprisinga mixture of macrocyclic modules and at least one polymeric component inorganic solvent.

[0027] In another aspect the invention provides compositions comprisinga thin film of a reaction product of macrocyclic modules and at leastone polymeric component, wherein the composition is prepared by aprocess comprising contacting the macrocyclic modules and the at leastone polymeric component at an air-liquid or liquid-liquid interface.

[0028] In another aspect the invention provides methods for makingnanofilm compositions. In one embodiment, a method for making a nanofilmcomposition comprising the reaction product of macrocyclic modules andat least one polymeric component comprises: (a) providing a mixture ofmacrocyclic modules and at least one polymeric component; and (b)forming the mixture into a thin film at an air-liquid or liquid-liquidinterface. In some embodiments, the polymeric component ispolymerizable, further comprising polymerizing the polymeric componentat the air-liquid or liquid-liquid interface. In another embodiment, amethod for making a nanofilm composition comprising the reaction productof macrocyclic modules and at least one polymeric component, comprises:(a) providing a subphase containing the at least one polymericcomponent; and (b) contacting macrocyclic modules with the surface ofthe subphase. In some embodiments, the method further comprises: (c)contacting a linker molecule with the surface of the subphase. Inanother embodiment, a method for making a nanofilm compositioncomprising the reaction product of macrocyclic modules and at least onepolymeric component, comprises: (a) providing a first liquid phasecomprising the macrocyclic modules; (b) providing a second liquid phasecomprising the at least one polymeric component; and (c) forming aliquid-liquid interface from the first liquid phase and the secondliquid phase.

[0029] In some embodiments, the nanofilm compositions may be prepared byspin coating, spray coating, dip coating, grafting, casting, phaseinversion, electroplating, or knife-edge coating.

[0030] In another aspect of the invention is provided methods forfiltration using the nanofilm compositions described herein. In oneembodiment, the method comprises using the nanofilm composition toseparate one or more components from a fluid. In another embodiment, themethod comprises using the nanofilm composition to separate one or morecomponents from a mixture of at least two gases.

BRIEF DESCRIPTION OF THE DRAWINGS

[0031] FIGS. 1(A-C) illustrates examples of ellipsometric images of ananofilm of Hexamer 1dh and poly(maleic anhydride-alt-1-octadecene)(PMAOD).

[0032] FIGS. 2(A-C) illustrates examples of ellipsometric images of ananofilm of Hexamer 1dh and PMAOD after sonication in various solvents.

[0033] FIGS. 3(A-D) illustrates examples of the surface rheometricstorage and loss moduli for a nanofilm of Hexamer 1dh and PMAOD.

[0034] FIGS. 4(A-D) illustrates examples of scanning electronmicrographs of a nanofilm of Hexamer 1dh and PMAOD on a polycarbonatesubstrate.

[0035] FIGS. 5(A-B) illustrates examples of scanning electronmicrographs of a polycarbonate substrate.

[0036]FIG. 6 illustrates an example of an attenuated total reflectanceFourier transform infrared (FTIR-ATR) spectrum of CHCl3 rinsings of ananofilm of PMAOD.

[0037]FIG. 7 illustrates an example of an FTIR-ATR spectrum of Hexamer1dh.

[0038]FIG. 8 illustrates an example of an FTIR-ATR spectrum of CHCl3rinsings of a nanofilm of Hexamer 1dh and PMAOD.

[0039]FIG. 9 illustrates an example of an FTIR-ATR spectrum of CHCl3rinsings of a nanofilm of Hexamer 1dh prepared on a water subphasecontaining diethyl malonimidate (DEM).

[0040]FIG. 10 illustrates an example of an FTIR-ATR spectrum of CHCl3rinsings of a nanofilm of Hexamer 1 dh and PMAOD prepared on a watersubphase containing DEM.

[0041]FIG. 11 illustrates examples of atomic force microscopy (AFM)images of a polycarbonate substrate.

[0042] FIGS. 12(A-B) illustrates examples of AFM images of a nanofilm ofHexamer 1dh and PMAOD on a (3-aminopropyl)triethoxysilane (APTES)modified SiO₂ substrate.

[0043]FIG. 13 illustrates examples of AFM images of a nanofilm ofHexamer 1dh and PMAOD prepared on a water subphase containing DEMdeposited on a polycarbonate substrate.

[0044]FIG. 14 illustrates examples of surface pressure-area isotherms ofa nanofilm of octadecylamine (ODA) and polymethylmethacrylate (PMMA).

[0045]FIG. 15 illustrates examples of surface pressure-area isotherms ofa nanofilm of ODA and PMAOD.

[0046]FIG. 16 illustrates examples of AFM images of a nanofilm ofHexamer 1dh and PMMA on a silicon substrate.

[0047]FIG. 17 illustrates examples of the surface rheometric storage andloss moduli for a nanofilm of Hexamer 1dh and PMAOD made on a subphasecontaining 2 mg/ml DEM.

[0048]FIG. 18 illustrates examples of the surface rheometric storage andloss moduli for a nanofilm of polyglycidyl methacrylate (PGM) made on asubphase containing 1% ethylene diamine compared with a nanofilm of PGMmade on a basic subphase.

[0049]FIGS. 19A and 19B show representations of examples of thestructure of embodiments of a hexamer macrocyclic module.

[0050]FIG. 20A shows an example of the Langmuir isotherm of anembodiment of a hexamer macrocyclic module.

[0051]FIG. 20B shows an example of the isobaric creep of an embodimentof a hexamer macrocyclic module.

[0052]FIG. 21A shows an example of the Langmuir isotherm of anembodiment of a hexamer macrocyclic module.

[0053]FIG. 21B shows an example of the isobaric creep of an embodimentof a hexamer macrocyclic module.

DETAILED DESCRIPTION OF THE INVENTION

[0054] Definitions

[0055] As used herein, the tenn “reaction product” refers to a productformed from the indicated components. Coupling may or may not occurbetween the components in forming a reaction product. Polymericcomponents may or may not be polymerized in forming a reaction product.In a non-limiting example, a nanofilm comprising a reaction product ofmacrocyclic modules and a polymeric component may have coupling betweenthe modules, and/or coupling between the modules and the polymericcomponent, and/or coupling between the polymeric components, or may haveno coupling at all. In some cases, the polymeric components arepolymerized. The polymeric components may be fully or partiallypolymerized. Alternatively, the polymeric components may not bepolymerized.

[0056] As used herein, the term “synthon” refers to a monomericmolecular unit from which a macrocyclic module may be made; amacrocyclic module is a closed ring of coupled synthons. Structures aridsyntheses of synthons and macrocyclic modules are described in greaterdetail hereinbelow.

[0057] As used herein, the terms “polymer” and “polymeric molecule”refer to a polymer or a molecule which is predominantly a polymer, butmay have some non-polymer atoms or species attached. The term polymerincludes copolymers, terpolymers, and polymers containing any number ofdifferent monomers.

[0058] As used herein, the term “polymeric component” refers to amolecule or species which is either a polymer, or may form a polymer bypolymerization. A polymerizable monomer or polymerizable molecule may bea polymeric component. In some cases, the polymeric component may beamphiphilic.

[0059] As used herein, “polymerizable” indicates a molecular specieswhich may polymerize under the reaction conditions in which the nanofilmis prepared. “Non-polymerizable” is used herein to indicate a molecularspecies which will not polymerize under the reaction conditions in whichthe nanofilm is prepared. A species which is “non-polymerizable” underone set of reaction conditions may be “polymerizable” under another setof reaction conditions.

[0060] As used herein, the terms “amphiphile” or “amphiphilic” refer toa molecule or species which exhibits both hydrophilic and lipophiliccharacter. In general, an amphiphile contains a lipophilic moiety and ahydrophilic moiety. The terms “lipophilic” and “hydrophobic” areinterchangeable as used herein. An amphiphile may form a Langmuir film.An amphiphile may be polymerizable. Alternatively, the amphiphile maynot be polymerizable.

[0061] Non-limiting examples of hydrophobic groups or moieties includelower alkyl groups, alkyl groups having 7, 8, 9, 10, 11, 12, or morecarbon atoms, including alkyl groups with 14-30, or 30 or more carbonatoms, substituted alkyl groups, alkenyl groups, alkynyl groups, arylgroups, substituted aryl, saturated or unsaturated cyclic hydrocarbons,heteroaryl, heteroarylalkyl, heterocyclic, and corresponding substitutedgroups. A hydrophobic group may contain some hydrophilic groups orsubstituents insofar as the hydrophobic character of the group is notoutweighed. In further variations, a hydrophobic group may includesubstituted silicon atoms, and may include fluorine atoms. Thelipophilic moieties may be linear, branched, or cyclic.

[0062] Non-limiting examples of groups which may be coupled to a synthonor macrocyclic module as a lipophilic group include alkyls, —CH═CH—R,—C≡C—R, —OC(O)—R, —C(O)O—R, —NHC(O)—R, —C(O)NH—R, and —O—R, where R is4-18C alkyl.

[0063] Non-limiting examples of hydrophilic groups or moieties includehydroxyl, methoxy, phenol, carboxylic acids and salts thereof, methyl,ethyl, and vinyl esters of carboxylic acids, amides, amino, cyano,isocyano, nitrile, ammonium salts, sulfonium salts, phosphonium salts,mono- and di-alkyl substituted amino groups, polypropyleneglycols,polyethylene glycols, epoxy groups, acrylates, sulfonamides, nitro,—OP(O)(OCH₂CH₂N⁺RR′R″)O⁻, guanidinium, aminate, acrylamide, pyridinium,piperidine, and combinations thereof, wherein R, R′ and R″ are eachindependently selected from H or alkyl. A hydrophilic group may containsome hydrophobic groups or substituents insofar as the hydrophiliccharacter of the group is not outweighed. Further examples includepolymethylene chains substituted with alcohol, carboxylate, acrylate,methacrylate, or

[0064] groups, where y is 1-6. Hydrophilic moieties may also includealkyl chains having internal amino or substituted amino groups, forexample, internal —NH—, —NC(O)R—, or —NC(O)CH═CH₂— groups. Hydrophilicmoieties may also include polycaprolactones, polycaprolactone diols,poly(acetic acid)s, poly(vinyl acetates)s, poly(2-vinyl pyridine)s,cellulose esters, cellulose hydroxyl ethers, poly(L-lysinehydrobromide)s, poly(itaconic acid)s, poly(maleic acid)s,poly(styrenesulfonic acid)s, poly(aniline)s, or poly(vinyl phosphonicacid)s.

[0065] As used herein, the terms “coupling” and “coupled” with respectto molecular moieties or species, polymeric components, synthons, andmacrocyclic modules refers to their attachment or association with othermolecular moieties or species, molecules, synthons, or macrocyclicmodules. The attachment or association may be specific or non-specific,reversible or non-reversible, the result of chemical reaction, orcomplexation. The bonds formed by a coupling reaction are often covalentbonds, or polar-covalent bonds, or mixed ionic-covalent bonds, and maysometimes be Coulombic forces, ionic or electrostatic forces orinteractions. In some preferred embodiments, the bonds formed by acoupling reaction are covalent.

[0066] As used herein, the terms “R,” “R′,” “R″”, and “R″” in a chemicalformula refer to a hydrogen or a functional group, each independentlyselected, unless stated otherwise. In some preferred embodiments, thefuinctional group may be an organic group.

[0067] As used herein, the term “functional group” includes, but is notlimited to, chemical groups, organic groups, inorganic groups,organometallic groups, aryl groups, heteroaryl groups, cyclichydrocarbon groups, amino (—NH₂), hydroxyl (—OH), cyano (—C≡N), nitro(—NO₂), carboxyl (—COOH), formyl (—CHO), keto (—CH₂C(O)CH₂—), alkenyl(—C═C—), alkynyl, (—C≡C—), and halo (F, Cl, Br and I) groups. In someembodiments, the functional group is an organic group.

[0068] As used herein, the term “alkyl” refers to a branched orunbranched monovalent hydrocarbon radical. An “n-mC” alkyl or“(nC-mC)alkyl” refers to all alkyl groups containing from n to m carbonatoms. For example, a 1-4C alkyl refers to a methyl, ethyl, propyl, orbutyl group. All possible isomers of an indicated alkyl are alsoincluded. Thus, propyl includes isopropyl, butyl includes n-butyl,isobutyl and t-butyl, and so on. An alkyl group with from 1-6 carbonatoms is referred to as “lower alkyl.” The term alkyl includessubstituted alkyls. As used herein, the term “substituted alkyl” refersto an alkyl group with an additional group or groups attached to anycarbon of the alkyl group. Additional groups attached to a substitutedalkyl may include one or more functional groups such as alkyl, loweralkyl, aryl, acyl, halogen, alkylhalo, hydroxy, amino, alkoxy,alkylamino, acylamino, acyloxy, aryloxy, aryloxyalkyl, mercapto, bothsaturated and unsaturated cyclic hydrocarbons, heterocycles, and others.

[0069] As used herein, the term “alkenyl” refers to any structure ormoiety having the unsaturation C═C. As used herein, the term “alkynyl”refers to any structure or moiety having the unsaturation C≡C.

[0070] As used herein, the term “aryl” refers to an aromatic group whichmay be a single aromatic ring or multiple aromatic rings which are fusedtogether, linked covalently, or linked to a common group such as amethylene, ethylene, or carbonyl, and includes polynuclear ringstructures. An aromatic ring or rings may include substituted orunsubstituted phenyl, naphthyl, biphenyl, diphenylmethyl, andbenzophenone groups, among others. The term “aryl” includes substitutedaryls.

[0071] As used herein, the term “substituted aryl” refers to an arylgroup with an additional group or groups attached to any carbon of thearyl group. Additional groups may include one or more functional groupssuch as lower alkyl, aryl, acyl, halogen, alkylhalos, hydroxy, amino,alkoxy, alkylamino, acylamino, acyloxy, aryloxy, aryloxyalkyl,thioether, heterocycles, both saturated and unsaturated cyclichydrocarbons which are fused to the aromatic ring(s), linked covalentlyor linked to a common group such as a methylene or ethylene group, or acarbonyl linking group such as in cyclohexyl phenyl ketone, and others.

[0072] As used herein, the term “heteroaryl” refers to an aromaticring(s) in which one or more carbon atoms of the aromatic ring(s) aresubstituted by a heteroatom such as nitrogen, oxygen, or sulfur.Heteroaryl refers to structures which may include a single aromaticring, multiple aromatic rings, or one or more aromatic rings coupled toone or more nonaromatic rings. It includes structures having multiplerings, fused or unfused, linked covalently, or linked to a common groupsuch as a methylene or ethylene group, or linked to a carbonyl as inphenyl pyridyl ketone. As used herein, the term “heteroaryl” includesrings such as thiophene, pyridine, isoxazole, phthalimide, pyrazole,indole, fuiran, or benzo-fused analogues of these rings.

[0073] As used herein, the term “acyl” refers to a carbonyl substituent,—C(O)R, where R is alkyl or substituted alkyl, aryl or substituted aryl,which may be called an alkanoyl substituent when R is alkyl.

[0074] As used herein, the term “amino” refers to a group —NRR′, where Rand R′ may independently be hydrogen, lower alkyl, substituted loweralkyl, aryl, substituted aryl or acyl.

[0075] As used herein, the term “alkoxy” refers to an —OR group, where Ris an alkyl, substituted lower alkyl, aryl, substituted aryl. Alkoxygroups include, for example, methoxy, ethoxy, phenoxy, substitutedphenoxy, benzyloxy, phenethyloxy, t-butoxy, and others.

[0076] As used herein, the term “thioether” refers to the generalstructure R—S—R′ in which R and R′ are the same or different and may bealkyl, aryl or heterocyclic groups. The group —SH may also be referredto as “sulfhydryl” or “thiol” or “mercapto.”

[0077] As used herein, the term “saturated cyclic hydrocarbon” refers toring structures such as cyclopropyl, cyclobutyl, cyclopentyl, andothers, including substituted groups. Substituents to saturated cyclichydrocarbons include substituting one or more carbon atoms of the ringwith a heteroatom such as nitrogen, oxygen, or sulfur. Saturated cyclichydrocarbons include bicyclic structures such as bicycloheptanes andbicyclooctanes, and multicyclic structures.

[0078] As used herein, the term “unsaturated cyclic hydrocarbon” refersto nonaromatic cyclic groups with at least one double bond, such ascyclopentenyl, cyclohexenyl, and others, including substituted groups.Substituents to unsaturated cyclic hydrocarbons include substituting oneor more carbon atoms of the ring with a heteroatom such as nitrogen,oxygen, or sulfur. Unsaturated cyclic hydrocarbons include bicyclicstructures such as bicycloheptenes and bicyclooctenes, and multicyclicstructures.

[0079] As used herein, the term “cyclic hydrocarbon” includessubstituted and unsubstituted, saturated and unsaturated cyclichydrocarbons, and includes unicyclic and multicyclic structures.

[0080] As used herein, the term “heteroarylalkyl” refers to alkyl groupsin which the heteroaryl group is attached through an alkyl group.

[0081] As used herein, the term “heterocyclic” refers to a saturated orunsaturated nonaromatic group having a single ring or multiple condensedrings comprising from 1-12 carbon atoms and from 1-4 heteroatomsselected from nitrogen, phosphorous, sulfur, or oxygen within the ring.Examples of heterocycles include tetrahydrofuran, morpholine,piperidine, pyrrolidine, and others.

[0082] As used herein, each chemical term described above expresslyincludes the corresponding substituted group. For example, the term“heterocyclic” includes substituted heterocyclic groups.

[0083] As used herein, the term “activated acid” refers to a —C(O)Xmoiety, where X is a leaving group, in which the X group is readilydisplaced by a nucleophile to form a covalent bond between the —C(O)—and the nucleophile. Examples of activated acids include acid chlorides,acid fluorides, p-nitrophenyl esters, pentafluorophenyl esters, andN-hydroxysuccinimide esters.

[0084] As used herein, the term “amino acid residue” refers to theproduct formed when a species comprising at least one amino (—NH₂) andat least one carboxyl (—C(O)O—) group couples through either of itsamino or carboxyl groups with an atom or functional group of a synthon.Whichever of the amino or carboxyl groups is not involved in thecoupling may optionally be blocked with a removable protective group.

[0085] Nanofilm Components

[0086] In one aspect, this invention relates variously to nanotechnologyin the preparation of porous structures and materials having pores thatare of atomic to molecular size. Materials such as nanofilm compositionsmay be formed from macrocyclic modules. Nanofilm compositions may alsobe formed from macrocyclic modules in combination with one or morepolymeric components. Nanofilm compositions may also be formed from apolymer and an amphiphile, wherein the amphiphile may be polymerizableor non-polymerizable. Nanofilm compositions may also be formed frompolymeric components which have been coupled through linkers. In someembodiments, pores may be supplied through the structure of thenanofilm. In some embodiments, pores are supplied through the structureof the macrocyclic modules.

[0087] In some variations, the nanofilm is prepared from coupledmacrocyclic modules, which may also be coupled to one or more polymericcomponents. In other variations, the nanofilm includes amphiphilicmolecules, which optionally may be coupled to any of the othercomponents. These amphiphilic molecules may be polymerizable ornon-polymerizable. It is to be understood that a “non-polymerizable”amphiphile is non-polymerizable under the reaction conditions in whichthe nanofilm is prepared.

[0088] A nanofilm may be prepared with mixtures of different modules, orwith mixtures of macrocyclic modules, amphiphilic molecules, and/orpolymeric components. In these variations, the polymeric component maybe intermixed, aggregated, or phase separated from the macrocyclicmodules and amphiphilic molecules, as described herein. Nanofilms havingone or more polymeric components made with mixtures of different modulesand/or amphiphilic molecules may also have interspersed arrays of poresof various sizes.

[0089] These materials may have regions in which unique structuresexist. The unique structures may repeat at regular intervals to providea lattice of pores having substantially uniform dimensions. The uniquestructures may have a variety of shapes and sizes, thereby providingpores of various shapes and sizes. Because the unique structures may beformed in a monolayer of molecular thickness, the pores defined by theunique structures may include a cavity, opening, or chamber-likestructure of molecular size. In general, pores of atomic to molecularsize defined by those unique structures may be used for selectivepermeation or molecular sieving functions. Some aspects ofnanotechnology are given in Nanostructured Materials, J. Ying, ed.,Academic Press, San Diego, 2001.

[0090] The nanofilm may have one or more polymeric components. Thesenanofilms may have regions composed primarily of one or more polymericcomponents. In some cases, the polymeric components act as aplasticizer. In some cases, regions composed primarily of one or morepolymeric components may form a barrier to permeation by fluids, smallmolecules, biomolecules, solvent molecules, or ions. In other cases, theporosity of the nanofilm is controlled by the type and degree ofcross-linking of the polymeric components.

[0091] A wide variety of structural features and properties such asamorphous, glassy, semicrystalline or crystalline structures, andelastomeric, pliable, thermoplastic, or deformation properties may beexhibited by the nanofilms.

[0092] The various components, such as, for example, modules andpolymeric components, may be deposited on a surface to form a nanofilm.Macrocyclic modules can be oriented on a surface by providing functionalgroups on the modules which impart amphiphilic character to the modules.For example, when the module is deposited on a hydrophilic surface,hydrophobic substituent groups or hydrophobic tails attached to themodule may cause the module to reorient on the surface so that thehydrophobic substituents are oriented away from the surface, leaving amore hydrophilic facet of the module oriented toward the surface. Othercomponents may also optionally similarly be oriented on the surface byproviding amphiphilic groups in the component.

[0093] The conformation of a molecule on a surface may depend on theloading, density, or state of the phase or layer in which the moleculeresides on the surface. Surfaces which may be used to orient modules orother molecules include interfaces such as gas-liquid, air-water,immiscible liquid-liquid, liquid-solid, or gas-solid interfaces. Thethickness of the oriented layer may, in some cases, be substantially amonomolecular layer thickness.

[0094] The composition of the nanofilm may be solid, gel, or liquid. Themodules of the nanofilm may be in an expanded state, a liquid state, ora liquid-expanded state. The state of the modules of the nanofilm may becondensed, liquid-condensed, collapsed, or may be a solid phase orclose-packed state. The modules and/or other components of the nanofilmmay interact with each other by weak forces of attraction.Alternatively, they may be coupled through, for example, covalent bonds.For example, the modules of a nanofilm prepared from surface-orientedmacrocyclic modules need not be linked by any strong interaction orcoupling. Alternatively, for example, the modules of the nanofilm may belinked through, for example, covalent bonds.

[0095] This invention further includes the rational design of moleculesor macrocyclic modules that may be assembled as “building blocks” forfurther assembly into larger species. Standardized molecular subunits ormodules may be used from which hierarchical molecules of predictedproperties can be assembled. Coupling reactions can be employed tocombine or attach modules in directed syntheses.

[0096] The preparation of macrocyclic modules beginning with a set ofsynthons is described in U.S. patent application Ser. Nos. 10/071,377and 10/226,400, and in the PCT Application entitled “Macrocyclic modulecompositions” filed Feb. 7, 2003, incorporated by reference herein intheir entirety. The assembly of molecular building blocks, beginningwith a set of synthons assembled to make macrocyclic modules, which, inturn, are combined to form a nanofilm are described in U.S. Serial No.60/383,236, filed May 22, 2002, and in U.S. patent application entitled“Nanofilm and Membrane Compositions” filed Feb. 7, 2003, incorporated byreference herein in their entirety. Examples and syntheses of synthons,macrocyclic modules, and amphiphilic macrocyclic modules are furtherdescribed hereinbelow.

[0097] Examples of modules useful as molecular building blocks are shownin Table 1. Examples of macrocyclic modules MODULE STRUCTURE Hexamer 1a

Hexamer 1dh

Hexamer 3j- amine

Hexamer 1jh-AC

Hexamer 1jh-

Hexamer 2j- amine/ester

Hexamer 1dh-

Octamer 5jh-

Octamer 4jh- acryl

[0098] Nanofilm Polymeric Components

[0099] In one aspect, this invention relates variously to nanofilmcompositions having polymeric components. Polymeric components may beintroduced into nanofilm compositions which contain macrocyclic modules.Nanofilm compositions may also be made from polymeric components coupledby linker molecules. Nanofilm compositions may also be made frompolymeric components and amphiphilic molecules, wherein the amphiphilicmolecules may optionally be polymerizable.

[0100] A polymeric component is a polymerizable species, or a polymer ormacromolecule of any molecular weight which is made of monomers.Polymerizable species include monomers, which are molecules that can berepeated in a polymer, and polymers, wherein the monomers or polymershave polymerizable or crosslinkable groups. Any polymeric component,polymerizable species, polymer, or monomer may also be amphiphilic.Examples of polymeric components include organic polymers,thermoplastics, synthetic and natural elastomers, conducting polymers,synthetic and natural biopolymers, and inorganic polymers. Examples ofpolymeric components of this invention include organic polymerscontaining atoms selected from H, C, N, O, S. F, and Cl.

[0101] The polymeric component may be a homopolymer, or a mixed, block,or graft copolymer. Mixed polymers, block polymers, and copolymersinclude macromolecules having two, three, or more different monomers.The polymeric component may have any combination of the monomers orpolymers which make up any of the example polymers described herein, ormay be a blend of polymers. Mixtures of polymeric components may be usedin variations of this invention. Examples of polymers include linear orbranched, side-chain branched, or branched comb polymers. A polymer maybe a star or dendrimeric form, or forms including microtubules,cylinders, or nanotubes of various compositions. Polymer branches may belong-chain branches or short-chain branches. The polymers may be made bysynthetic methods, or may be obtained from naturally-occurring sources.

[0102] A polymeric component may be in the form of a polymer whenintroduced into the mixture used to form a nanofilm. In some variations,a polymeric component which is already in the form of a polymer whenintroduced into the mixture used to form a nanofilm may have amphiphiliccharacter. A polymer having amphiphilic character may be more soluble inwater than organic solvent, or vice-versa. In some variations, apolymeric component may be a water soluble polymer having polar groupsand amphiphilic character.

[0103] In further variations, the polymeric component may be in the formof a polymerizable molecule when introduced into the mixture used toform a nanofilm. Polymerizable molecules used to prepare a nanofilminclude monomers. In some variations, polymerizable molecules used toprepare a nanofilm may have amphiphilic character. The polymericcomponent of a nanofilm may be formed in-situ during preparation of thenanofilm from macrocyclic modules and/or other components. In-situformation of the polymeric component of a nanofilm may be carried out bypolymerization of a monomer or polymerizable amphiphile in amulticomponent mixture.

[0104] Examples of a polymeric component include poly(maleicanhydrides), a copolymer of maleic anhydride, poly(ethylene-co-maleicanhydride), poly(maleic anhydride-co-alpha olefin), polyacrylates, apolymer or copolymer having acrylate side groups, a polymer or copolymerhaving oxacyclopropane side groups, polyethyleneimides, polyetherimides,polyethylene oxides, polypropylene oxides, polystyrenes, poly(vinylacetate)s, polytetrafluoroethylenes, polyolefins, polyethylenes,polypropylenes, ethylene-propylene copolymers, polyisoprenes,neopropenes, polyanilines, polyacetylenes, polyvinylchlorides,polyvinylidene chlorides, polyvinylidene fluorides, polyvinylalcohols,polyurethanes, polyamides, polyimides, polysulfones, polyethersulfones,polysulfonamides, polysulfoxides, polyglycolic acids, polyacrylamides,polyvinylalcohols, polyesters, polyester ionomers, polyethyleneterephthalates, polybutylene terephthalates, polycarbonates,polysorbates, polylysines, polypeptides, poly(amino acids),polyvinylpyrrolidones, polylactic acids, gels, hydrogels, carbohydrates,polysaccharides, agarose, amylose, amylopectin, glycogen, dextran,cellulose, cellulose acetates, chitin, chitosan, peptidoglycan, andglycosaminoglycan. Examples of a polymeric component also includeamino-branched, amino-substituted, and amino-terminal derivatives of thepreceding example polymers. Other examples of a polymeric componentinclude polynucleotides, synthetic or naturally-occurringpolynucleotides, for example, poly(T) and poly(A), nucleic acids, aswell as proteoglycans, glycoproteins, and glycolipids.

[0105] Examples of polymeric components which are polymerizable monomersinclude vinyl halide compounds such as vinyl chloride; vinylidenemonomers such as vinylidene chloride; unsaturated carboxylic acids suchas acrylic acid, methacrylic acid, maleic acid, itaconic acid, and saltsthereof; acrylates such as methyl acrylate, ethyl acrylate, butylacrylate, octyl acrylate, methoxyethyl acrylate, phenyl acrylate andcyclohexyl acrylate; methacrylates such as methyl methacrylate, ethylmethacrylate, butyl methacrylate, octyl methacrylate, phenylmethacrylate and cyclohexyl methacrylate; unsaturated ketones such asmethyl vinyl ketone, ethyl vinyl ketone, phenyl vinyl ketone, methylisobutenyl ketone and methyl isopropenyl ketone; vinyl esters such asvinyl formate, vinyl acetate, vinyl propionate, vinyl butyrate, vinylbenzoate, vinyl monochloroacetate, vinyl dichloroacetate, vinyltrichloroacetate, vinyl monofluoroacetate, vinyl difluoroacetate andvinyl trifluoroacetate; vinyl ethers such as methyl vinyl ether andethyl vinyl ether; acrylamide and alkyl substituted compounds thereof;acid compounds containing a vinyl group and salts, anhydrides andderivatives thereof such as vinylsulfonic acid, allylsulfonic acid,methallylsulfonic acid, styrenesulfonic acid,2-acrylamido-2-methylpropanesulfonic acid, sulfopropyl methacrylate,vinylstearic acid and vinylsulfinic acid; styrene or alkyl- orhalogen-substituted compounds thereof such as styrene, methylstyrene andchlorostyrene; allyl alcohol or esters or ethers thereof; vinylimidessuch as N-vinylphthalimide and N-vinylsuccinoimide; basic vinylcompounds such as vinylpyridine, vinylimidazole, dimethylaminoethylmethacrylate, N-vinylpyrrolidone, N-vinylcarbazole and vinylpyridine;unsaturated aldehydes such as acrolein and methacrolein; andcross-linking vinyl compounds such as glycidyl methacrylate,N-methylolacrylamide, hydroxyethyl methacrylate, triallyl isocyanurate,triallyl cyanurate, divinylbenzene, ethylene glycol di(meth)acrylate,diethylene glycol di(meth)acrylate, triethylene glycol di(meth)acrylate, trimethylolpropane tri (meth)acrylate and methylenebisacrylamide.

[0106] Examples of polymeric components which are polymerizableamphiphiles include long chain alkyl derivatives of vinyl halides,vinylidene halides, unsaturated carboxylic acids and salts thereof,acrylates, methacrylates, unsaturated ketones, vinyl esters, vinylethers, acrylamides, acid compounds containing a vinyl group,anhydrides, styrenes, allyl alcohol or esters or ethers thereof,vinylimides, vinyl compounds, unsaturated aldehydes, and vinylcompounds. Examples of polymeric components which are polymerizableamphiphiles generally include amphiphilic acrylates, amphiphilicacrylamides, amphiphilic vinyl esters, amphiphilic anilines, amphiphilicdiynes, amphiphilic dienes, amphiphilic acrylic acids, amphiphilic enes,amphiphilic cinnamic acids, amphiphilic amino-esters, and amphiphilicoxiranes. Further examples of polymeric components which arepolymerizable amphiphiles include amphiphilic amines, amphiphilicdiesters, amphiphilic diacids, amphiphilic diols, amphiphilic polyols,and amphiphilic diepoxides, any of which may be coupled with linkermolecules.

[0107] Preferred polymeric components include poly(maleicanhydride-co-alpha olefin), PMAOD, PMMA, poly(2-hydroxyethylmethacrylate) (PHEMA), PGM, polyethylene imine (PEI) andCH₂═CHC(O)OCH₂CH₂OH. Further preferred polymeric components which may beused in the nanofilms of the invention include those described in Tables5-9 hereinbelow. In some embodiments, the polymeric component ispoly(maleic anhydride-co-alpha olefin). In some embodiments, thepolymeric component is PMAOD. In some embodiments, the polymericcomponent is PMMA. In some embodiments, the polymeric component isPHEMA. In some embodiments, the polymeric component is PGM. In someembodiments, the polymeric component is PEI. In some embodiments, thepolymeric component is CH₂═CHC(O)OCH₂CH₂OH.

[0108] A polymeric component may have an atom or a group of atoms whichcouple to other species or components of a nanofilm. Coupling of thepolymeric component to other species in a nanofilm may be complete orincomplete. The polymeric component may couple to macrocyclic modules orlinker molecules, or to other polymeric components, or to other speciessuch as amphiphiles or monomers. Coupling of macrocyclic modules, linkermolecules, or other species may be to domains of the polymericcomponent, occurring at the interface or surface of the domains.

[0109] Nanoflims of Amphiphilic Molecules

[0110] Amphiphilic molecules may be oriented on a surface such as anair-water interface in a Langmuir trough, and may be compressed to forma Langmuir thin film. The amphiphilic molecules of the Langmuir thinfilm may be coupled to each other or to other components, and may form asubstantially monomolecular layer thin film material.

[0111] Non-limiting examples of polar groups of the amphiphilicmolecules include amide, amino, ester, —SH, acrylate, acrylamide, epoxy,—OH, —OCH₃, —NH₂, —CN, —NO₂, —N⁺RR′R″, —SO₃ ⁻, —OPO₂ ²⁻, —OC(O)CH═CH₂,—SO₂NH₂, —SO₂NRR′, —OP(O)(OCH₂CH₂N⁺RR′R″)O⁻, —C(O)OH, —C(O)O⁻,guanidinium, aminate, pyridinium, —C(O)OCH₃, —C(O)OCH₂CH₃,

[0112] where w is 1-6, —C(O)OCH═CH₂, —O(CH₂)_(x)C(O)NH₂, where x is 1-6,—O(CH₂)_(y)C(O)NHR, where y is 1-6, and —O(CH₂CH₂O)_(z)R, where z is1-6, and hydrophilic groups. The polar groups may be coupled together bycoupling reactions to form a thin film material. The polar groups of theamphiphilic molecules may be linked directly to each other. For example,sulfhydryl groups may be coupled to form disulfide link, or polar groupshaving ester and amino groups may couple to attach the amphiphilicmolecules through amide linkages. The coupling may attach more than twoamphiphilic molecules, for example, by extended amide linkages. Thepolar groups of the amphiphilic molecules may also be linked to eachother with a linker molecule. For example, amino may be coupled by theMannich reaction with formaldehyde. A portion of the amphiphilicmolecules of the nanofilm may be coupled, while the rest are notcoupled. The amphiphilic molecules of the nanofilm, both those which arecoupled and those which are not coupled, may also interact through weaknon-bonding or bonding interactions such as hydrogen bonding and otherinteractions.

[0113] The hydrophobic tails of the amphiphilic molecules may be anylength, and are sometimes from about 1 to 28 carbon atoms. Examples ofhydrophobic tails of the amphiphilic molecules include the hydrophobicgroups which may be attached to macrocyclic modules to impartamphiphilic character to the modules.

[0114] Preferred polymerizable amphiphiles include amphiphilicacrylates, amphiphilic acrylamides, amphiphilic vinyl esters,amphiphilic anilines, amphiphilic diynes, amphiphilic dienes,amphiphilic acrylic acids, amphiphilic enes, amphiphilic cinnamic acids,amphiphilic amino-esters, amphiphilic oxiranes, amphiphilic amines,amphiphilic diesters, amphiphilic diacids, amphiphilic diols,amphiphilic polyols, and amphiphilic diepoxides.

[0115] Preferred non-polymerizable amphiphiles include decylamine andstearic acid. It is to be understood that these are “non-polymerizableamphiphiles” when they are non-polymerizable under the conditions inwhich the nanofilm is prepared. These may be considered polymerizableamphiphiles when included in other nanofilms, wherein the conditions ofthe preparation of those nanofilms could cause the amphiphiles to bepolymerized.

[0116] In some embodiments, the amphiphile may be octadecylamine (ODA).In some embodiments, the amphiphile may be methylheptadecanoate (MHD).In some embodiments, the amphiphile may be N-octadecylacrylamide (ODAA).In some embodiments, the amphiphile may be decylamine. In someembodiments, the amphiphile may be stearic acid. In some embodiments,the amphiphile may be a methyl ester of stearic acid. In someembodiments, the amphiphile may be icosanol, or other long chainalkanol. Further examples of preferred amphiphiles may be found in theExamples, and in Tables 5-9.

[0117] Pores and barrier properties are found in the structure of thenanofilm made by coupling amphiphilic molecules. The pores and barrierproperties may be modified by the degree or extent of coupling orinteraction of the amphiphilic molecules, and for example, by the lengthof the linker molecules.

[0118] Coupling of Macrocyclic Modules and other Components

[0119] Macrocyclic modules and/or other components oriented on a surfacemay be coupled to form a thin layer composition or nanofilm. Forexample, surface-oriented modules may be coupled in a two-dimensionalarray to form a substantially monomolecular layer nanofilm. Thetwo-dimensional array is generally one molecule thick throughout thethin layer composition, and may vary locally due to physical andchemical forces. Coupling of modules and/or other components may be doneto form a substantially two-dimensional thin film by orienting themodules and/or other components on a surface before or during theprocess of coupling. In general, amphiphilic components may be orientedon an interface. In general, water soluble components may be added tothe subphase for the formation of a nanofilm. Components may also bemixed prior to orienting on an interface.

[0120] Macrocyclic modules can be prepared to possess functional groupswhich permit coupling of the modules. The nature of the products formedby coupling modules depends, in one variation, on the relativeorientations of the functional groups with respect to the modulestructure, and in other variations on the arrangement of complementaryfunctional groups on different modules which can form covalent,non-covalent or other binding attachments with each other.

[0121] In some variations, a macrocyclic module includes functionalgroups which couple directly to complementary functional groups of othermacrocyclic modules to form linkages between macrocyclic modules. Thefunctional groups may in some cases contribute to the amphiphiliccharacter of the module before or after coupling, and may be covalentlyor non-covalently attached to the modules. In some embodiments, thefunctional groups are covalently attached to the modules. The functionalgroups may be attached to the modules before, during, or afterorientation of the modules on the surface.

[0122] In other variations, a macrocyclic module includes functionalgroups which couple to polymeric components and/or other components.Macrocyclic modules may be prepared with functional groups which coupleto complementary functional groups of polymeric and/or other componentsto form linkages. The coupling between macrocyclic modules and theseother components may be direct, or may occur through linker molecules.

[0123] In other variations, components such as polymeric components andamphiphiles may also comprise functional groups for coupling tothemselves or to other components, such as coupling a polymericcomponent to another polymeric component, or coupling a polymericcomponent to an amphiphilic component. The functional groups may beattached to the components before, during, or after orientation of thecomponents on a surface or subphase. In some cases, the functionalgroups impart amphiphilic character to the component, either before orafter coupling.

[0124] In making nanofllms from macrocyclic modules and/or othercomponents, one or more coupling linkages may be formed betweenmacrocyclic modules, and coupling may occur between macrocyclic modulesand other components. In some variations, coupling may also occurbetween other components, for example, between amphiphilic groups andpolymeric components. The linkage formed between, e.g., macrocyclicmodules or between a macrocyclic module and another component may be theproduct of the coupling of one functional group from each molecule. Forexample, a hydroxyl group of a first macrocyclic module may couple withan acid group or acid halide group of a second macrocyclic module toform an ester linkage between the two macrocyclic modules. Anotherexample is an imine linkage, —CH═N—, resulting from the reaction of analdehyde, —CH═O, on one macrocyclic module with an amine, —NH₂, onanother macrocyclic module. Examples of linkages between macrocyclicmodules or between macrocyclic modules and other components are shown inTable 2. TABLE 2 Examples of functional groups and linkages formedFunctional Group A Functional Group B Linkage Formed —NH₂ —C(O)H —N═CH——NH₂ —CO₂H —NHC(O)— —NHR —CO₂H —NRC(O)— —OH —CO₂H —OC(O)— -X —O Na —O——SH —SH —S—S— -X —(NR)Li —NR- -X —S Na —S— -X —NHR —NR- -X —CH₂CuLi—CH₂— -X —(CRR ″)_(n=1−6)CuLi —(CRR ″)_(n)— module-X module-Xmodule-module —CH₂X —CH₂X —CH₂CH₂— —ONa —C(O)OR —C(O)O— —SNa —C(O)OR—C(O)S— -X —C≡CH —C≡C— —C≡CH —C≡CH —C≡C—C≡C— —MgX —C(O)H —CH(OH)—module-NH₂

module-MgX

module-X

—C(O)H —C(O)H —HC═CH— (CH₃)₂C≡CH-module module-C(O)Cl

—N═C═O —NH₂ —NHC(O)NH— —N═C═O HO— —NHC(O)O— —C(O)H —NHNH₂ —CH═N—NH— —OH—OC(O)X —OC(O)O— (CH₃)₂C═CH-module module-SH

(CH₃)₂CHC(O)O-module module-CH(O)

module-CH₂C(O)OH module-CH₂C(O)OH

R₂SiH-module

—NH₂

[0125] In Table 2, R and R′ represent hydrogen or alkyl groups, and X ishalogen or other good leaving group. It is to be understood that thefunctional groups included in Table 2 may also be used to link a modulewith another component, such as a polymeric component, and may also beused to link non-module components together, such as a polymericcomponent to another polymeric component, or a polymeric component to anamphiphilic component.

[0126] In another variation, a macrocyclic module may have functionalgroups for coupling to other macrocyclic modules wherein the functionalgroups are coupled to the macrocyclic module after initial preparationof the closed ring of the module. For example, an amine linkage betweenthe synthons of a macrocyclic module may be substituted with one ofvarious functional groups to produce a substituted linkage. Examples ofsuch linkages between synthons of a macrocyclic module having functionalgroups for coupling other macrocyclic modules are shown in Table 3.TABLE 3 Examples of macrocyclic module linkages Macrocyclic ModuleLinkage Reagent Substituted Linkage

[0127] In Table 3, X is halogen, and Q represents a synthon in amacrocyclic module.

[0128] Referring to Table 3, the substituted linkage of a macrocyclicmodule may couple to a substituted linkage of another module. In somevariations, the coupling of these linkages is done by initiating 2+2cycloaddition. For example, acrylamide linkages may couple to produce

[0129] by 2+2 cycloaddition. In other variations, coupling of thesereactive substituted linkages may be initiated by other chemical,thermal, photochemical, electrochemical, and irradiative methods toprovide a variety of coupled structures. It is to be understood that thefunctional groups and substituted linkages formed included in Table 3may also be used to link a module with another component, such as apolymeric component, and may also be used to link non-module componentstogether, such as a polymeric component to an amphiphilic component.

[0130] The functional groups used to form linkages between macrocyclicmodules and/or other components may be separated from the module orcomponent by a spacer. A spacer can be any atom or group of atoms whichcouples the functional group to the macrocyclic module or othercomponent, and does not interfere with the linkage-forming reaction. Aspacer is part of the functional group, and becomes part of the linkagebetween macrocyclic modules and/or other components. An example of aspacer is a polymethylene group, —(CH2)n-, where n is 1-6. The spacermay be said to extend the linkage between macrocyclic modules and/orother components. Other examples of spacer groups are alkylene, aryl,acyl, alkoxy, saturated or unsaturated cyclic hydrocarbon, heteroaryl,heteroarylalkyl, heterocyclic, and corresponding substituted groups.Further examples of spacer groups are polymer, copolymer, or oligomerchains, for example, polyethylene oxides, polypropylene oxides,polysaccharides, polylysines, polypeptides, poly(amino acids),polyvinylpyrrolidones, polyesters, polyacrylates, polyamines,polyimines, polystyrenes, poly(vinyl acetate)s,polytetrafluoroethylenes, polyisoprenes, neopropene, polycarbonate,polyvinylchlorides, polyvinylidene fluorides, polyvinylalcohols,polyurethanes, polyamides, polyimides, polysulfones, polyethersulfones,polysulfonamides, polysulfoxides, and copolymers thereof. Examples ofpolymer chain spacer structures include linear, branched, comb anddendrimeric polymers, random and block copolymers, homo- andheteropolymers, flexible and rigid chains. The spacer may be any groupwhich does not interfere with formation of the linkage. A spacer groupmay be substantially longer or shorter than the functional group towhich it is attached.

[0131] Coupling of macrocyclic modules and/or other components to eachother may occur through coupling of functional groups of the macrocyclicmodules and/or other components to linker molecules. The functionalgroups involved may be, for example, those exemplified in Table 2. Forexample, modules may couple to at least one other module through alinker molecule. A linker molecule is a discrete molecular species usedto couple at least two modules. Each module may have 1 to 30 or morefunctional groups which may couple to a linker molecule. Linkermolecules may have 1 to 20 or more functional groups which may coupleto, for example, a module.

[0132] In one variation, a linker molecule has at least two functionalgroups, each of which can couple to a module and/or other component. Inthese variations, linker molecules may include a variety of functionalgroups for coupling modules and/or other components. Non-limitingexamples of functional groups of modules and linker molecules areillustrated in Table 4. TABLE 4 Examples of functional groups of modulesand linker molecules Functional Functional Group of Group of Module AModule B Linker Molecule Linkage —NHR or —NH₂ —NHR or —NH₂

—NHR or NH₂ —NHR or —NH₂

—NHR or —NH₂ —NHR or —NH₂

—NHR or —NH₂ —NHR or —NH₂

—OH —OH

—OH —OH

—OH —OH (RO)₂BR ′B(OR)₂ —O(HO)BR ′(OH)O— —NHR or —NHR or (RO)₂BR ′B(OR)₂—NH(HO)BR ′B(OH)NH— —NH₂ —NH₂ —OH —OH X-(CH₂)_(n)-X —O—(CH₂)_(n)—O— —OH—OH ClC(O)—(CH₂)_(n)—C(O)Cl

—NHR or —NH₂ —NHR or —NH₂

—NHR or —NH₂ —NHR or —NH₂

—OH —OH

—OCH₂CH(OH)CH₂O— —OH —NH₂

—OCH₂CH(OH)CH₂NH— —NH₂ —NH₂

—NHCH₂CH(OH)CH₂NH— —NRH —NRH

—NHCH₂CH(OH)CH₂NR—

[0133] In Table 4, n is 1-6, m is 1-10, R is —CH₃ or —H, R′ is—(CH₂)_(n)— or phenyl, R″ is —(CH₂)—, polyethylene glycol (PEG), orpolypropylene glycol (PPG), and X is Br, Cl, I, or other good leavinggroups which are organic groups containing atoms selected from the groupof carbon, oxygen, nitrogen, halogen, silicon, phosphorous, sulfur, andhydrogen. A module may have a combination of the various functionalgroups exemplified in Table 4. It is to be understood that thefunctional groups and linkers included in Table 4 may also be used tolink a module with another component, such as a polymeric component, andmay also be used to link nonmodule components together, such as apolymeric component to an amphiphilic component. Preferred linkersinclude DEM and ethylene diamine. Further examples of suitable linkersare found in the Examples, and in Tables 5-9.

[0134] Methods of initiating coupling of the modules and/or componentsto linker molecules include chemical, thermal, photochemical,electrochemical, and irradiative methods.

[0135] A nanofilm comprising coupled modules and/or other components canbe made by coupling together one or more members of the collection ofmodules and/or other components, perhaps with other bulky or flexiblecomponents, to form a thin layer nanofilm material or composition.Coupling of modules and/or other components may be complete orincomplete, providing a variety of structural variations useful asnanoflim membranes.

[0136] In general, the coupling of polymeric components to macrocyclicmodules to prepare a nanofilm may be done with myriad combinations ofcomplementary functional groups. For example, as shown herein,macrocyclic modules which may couple to other macrocyclic modulesthrough linker molecules may also couple to polymeric components andother components having complementary functional groups. In the variousschemes for the preparation of nanofilm with linker moleculesillustrated in Table 5 hereinbelow, a polymeric component having aminofunctional groups, for example, may couple to linker molecules andcompete with the macrocyclic modules for coupling to other macrocyclicmodules. In another example, a macrocyclic module having aminofunctional groups may couple to poly(ethylene-co-maleic anhydride) toform a maleimide group in the polymer. The various types and degrees ofcoupling depend on the identity of the functional groups of thepolymeric components.

[0137] When mixtures of polymerizable species are used to prepare ananofilm, the species may copolymerize. Copolymerization may involvecoupling to functional groups of macrocyclic modules.

[0138] The coupling of modules in a nanofilm may attach two or morecomponents by a linkage or linkages. The coupling may attach more thantwo modules, for example, by an array of linkages each formed betweentwo modules. Each module may form more than one linkage to anothermodule, and each module may form several types of linkages, includingthose exemplified in Tables 2-4. A module may have direct linkages,linkages through a linker molecule, and linkages which include spacers,in any combination. A linkage may connect any portion of a module to anyportion of another module. An array of linkages and an array of modulesmay be described in terms of the theory of Bravais lattices and theoriesof symmetry.

[0139] A portion of each of the components of aznanofilm may be coupled,while the remainder of each is not coupled. The components of thenanofilm may interact through, for example, hydrogen bonding, van derWaals, and other interactions. The arrangement of linkages formed in ananofilm may be represented by a type of symmetry, or may besubstantially unordered.

[0140] Nanofilms of Macrocyclic Modules and Polymeric Components

[0141] A nanofilm may be prepared from mixtures of macrocyclic modulesand other components. The types of coupling between the components andthe phase and domain behavior of the mixture, as described herein, mayinfluence the composition and properties of the product nanofilm.Multicomponent mixtures of these types sometimes result in phaseseparated or aggregated compositions. A macrocyclic module mayparticipate in more than one type of coupling, and the product nanofilmmay have a wide variety of compositions.

[0142] In one aspect, this invention relates to the introduction ofpolymeric components into nanofilms comprising macrocyclic modules.Various types of coupling may be used to prepare a nanofilm withmacrocyclic modules and polymeric components. In one type of coupling, amacrocyclic module may have functional groups which couple to a linkermolecule which, in turn, couples to another macrocyclic module or otherspecies, but may not effectively couple to a polymeric component. Inthis type of coupling, the macrocyclic module may couple much morerapidly to another macrocyclic module than to the polymeric component,and form a nanofilm in which the degree of coupling between macrocyclicmodules and the polymeric component is limited. For example, amacrocyclic module having amino functional groups may couple readilywith a linker molecule such as ClC(O)CH2C(O)Cl, but not as readily withsome polymeric components.

[0143] In another mode of coupling, a macrocyclic module may not havefunctional groups which readily couple to other components. An exampleof this type is a macrocyclic module having imine linkages and onlyalkyl substituents which may not readily couple to other macrocyclicmodules, polymeric components, or other species. A macrocyclic modulewhich does not readily couple to other species may form a nanofilm withpolymeric components without substantial coupling between macrocyclicmodules and polymeric components.

[0144] In one aspect, this invention involves the formation of ananofilm using multicomponent mixtures of macrocyclic modules andpolymeric components, wherein the macrocyclic modules may not directlycouple to other macrocyclic modules or to polymeric components informing the nanofilm, and wherein the macrocyclic modules may be coupledthrough linker molecules.

[0145] Various schemes for the preparation of nanofilms with linkermolecules are illustrated in Table 5. TABLE 5 Schemes to preparenanoflims from macrocyclic modules with linker molecules and polymericcomponents Reagents Scheme macrocyclic module linker molecule polymer

macrocyclic module linker molecule amphiphilic polymer

macrocyclic module linker molecule polymerizable amphiphile

macrocyclic module linker molecuel polymerizable monomer

Macrocyclic module linker molecule polymer amphiphile

macrocyclic module linker molecule polymer polymerizable amphiphile

macrocyclic module linker molecule polymer amphiphilic polymer

macrocyclic module linker molecule amphiphilic polymer polymerizableamphiphile

macrocyclic module linker molecule amphiphile polymerizable amphiphile

macrocyclic module linker molecule polymerizable amphiphilepolymerizable monomer

[0146] In Table 5, R is alkyl, and n is about 3 to 1,000,000. Referringto Table 5, in some schemes the multicomponent mixture of macrocyclicmodules may include a polymer, or an amphiphilic polymer, or mixturesthereof. In one scheme, for example, macrocyclic modules having aminofunctional groups are mixed with polymethylmethacrylate (PMMA), which isimmiscible with water. The macrocyclic modules are then coupled withlinker molecules ClC(O)CH2C(O)Cl. In schemes with such mixtures, themacrocyclic modules may not couple directly to polymeric components,except at interfaces between phases. Even where the macrocyclic modulesand polymeric components form a single continuous phase, the macrocyclicmodules may be coupled predominantly to other macrocyclic modules. Innanofilms where macrocyclic modules and polymeric components are phaseseparated, surface coupling and other adhesion of various domains mayoccur.

[0147] In other schemes illustrated in Table 5, multicomponent mixturesof macrocyclic modules used to prepare nanofilm may include a polymerand/or an amphiphilic polymer, and may further include a molecule whichis amphiphilic which may or may not be polymerizable, or a monomer whichis polymerizable, or mixtures thereof.

[0148] In other schemes illustrated in Table 5, multicomponent mixturesof macrocyclic modules used to prepare nanofilms may include apolymerizable amphiphile or a polymerizable monomer species, or mixturesthereof. These nanofilms may optionally include a non-polymerizableamphiphilic species.

[0149] In the schemes illustrated in Table 5, multicomponent mixtures ofmacrocyclic modules used to prepare nanofilm may optionally includeamphiphilic molecules which may have a functional group that can coupleto macrocyclic modules or to polymeric components.

[0150] In another aspect, this invention involves formation of nanofilmusing multicomponent mixtures of macrocyclic modules and polymericcomponents, where the macrocyclic modules may not readily couple to thepolymeric components or to other macrocyclic modules. Various schemesfor the preparation of such nanofilms are illustrated in Table 6. TABLE6 Schemes to prepare nanoflim from macrocyclic modules which may notreadily couple Reagents Scheme macrocyclic module polymer

macrocyclic module amphiphilic polymer

macrocyclic module polymerizable amphiphile

macrocyclic module polymerizable monomer

macrocyclic module polymer amphiphile

macrocyclic module polymer polymerizable amphiphile

macrocyclic module amphiphilic polymer polymerizable amphiphile

macrocyclic module amphiphile polymerizable amphiphile

macrocyclic module polymerizable amphiphile polymerizable monomer

[0151] In Table 6, n is about 3 to about 1,000,000. Referring to Table6, in some schemes the multicomponent mixture of macrocyclic modules mayinclude a polymer, or an amphiphilic polymer, or mixtures thereof. Inthese schemes, the macrocyclic modules may not readily couple topolymeric components or to other modules, but may undergo some degree ofcoupling to either the polymeric components or other modules. In theschemes illustrated in Table 6, multicomponent mixtures of macrocyclicmodules used to prepare nanofilm may include a polymer and/or anamphiphilic polymer, and may further include a molecule which isamphiphilic and may be polymerizable, or a monomer which ispolymerizable, or mixtures thereof.

[0152] In other schemes illustrated in Table 6, multicomponent mixturesof macrocyclic modules used to prepare nanofilms may include apolymerizable amphiphile or a polymerizable monomer species, or mixturesthereof. These nanofilms may optionally include a non-polymerizableamphiphilic species.

[0153] In the schemes illustrated in Table 6, multicomponent mixtures ofmacrocyclic modules used to prepare nanofilm may further includeamphiphilic molecules which may have a functional group that can coupleto macrocyclic modules or to polymeric components.

[0154] In another aspect, this invention relates to the formation ofnanofilms using multicomponent mixtures of macrocyclic modules andpolymeric components, wherein the macrocyclic modules may directlycouple to the polymeric components, or to other macrocyclic modules.Various schemes for the preparation of such nanofilms are illustrated inTable 7. TABLE 7 Schemes to prepare nanoflim with macrocyclic moduleswhich may undergo direct coupling Reagents Scheme macrocyclic modulepolymer

macrocyclic module and amphiphilic polyer: (a) prepare nanofilm layer ofcomponents (b) couple components

macrocyclic module polymerizable amphiphile

macrocyclic module polymerizable monomer

macrocyclic module polymer amphiphile

macrocyclic module polymer polymerizable amphiphile

macrocyclic module polymer amphiphilic polymer

macrocyclic module amphiphilic polymer polymerizable amphiphile

macrocyclic module polymerizable amphiphile amphiphile

macrocyclic module polymerizable amphiphile polymerizable monomer

macrocyclic module polymerizable monomer amphiphile

macrocyclic module and amphiphilic polymer: (a) couple in solution (b)prepare nanofilm

[0155] In Table 7, R is alkyl, and n is about 3 to about 1,000,000.Referring to Table 7, in some schemes the multicomponent mixture ofmacrocyclic modules may include a polymer, or an amphiphilic polymer, ormixtures thereof In these schemes, the macrocyclic modules may in somecases couple directly to polymeric components, and may form a singlephase.

[0156] In other schemes illustrated in Table 7, multicomponent mixturesof macrocyclic modules used to prepare nanofilm may include a polymerand/or an amphiphilic polymer, and may further include a molecule whichis amphiphilic which may or may not be polymerizable, or a monomer whichis polymerizable, or mixtures thereof.

[0157] In other schemes illustrated in Table 7, multicomponent mixturesof macrocyclic modules used to prepare nanofilms may include apolymerizable amphiphile or a polymerizable monomer species, or mixturesthereof These nanofilms may optionally include a non-polymerizableamphiphilic species.

[0158] In the schemes illustrated in Table 7, multicomponent mixtures ofmacrocyclic modules used to prepare nanofilm may also includeamphiphilic molecules which may have a functional group that can coupleto macrocyclic modules or to polymeric components.

[0159] The type of coupling in which a macrocyclic module participatesto form a nanofilm may depend on the presence of other components of thenanofilm. For example, a macrocyclic module with acrylate functionalgroups may couple much more rapidly to itself than to a polymericcomponent with less reactive groups.

[0160] A macrocyclic module may participate in more than one type ofcoupling. For example, a macrocyclic module which may couple directly toanother macrocyclic module may also couple through a linker molecule toanother macrocyclic module. Both types of coupling may occur in the samemulticomponent mixture used to prepare a nanofilm.

[0161] In one type of coupling, a macrocyclic module may have functionalgroups which couple directly to complementary functional groups ofanother macrocyclic module. An example of this form is a macrocyclicmodule having acrylamide functional groups. In this type of coupling,the macrocyclic module may couple much more rapidly to anothermacrocyclic module than to any polymeric component, and form a nanofilmin which the degree of coupling between macrocyclic modules and thepolymeric component is limited.

[0162] In some variations, the polymeric component may havecomplementary functional groups which effectively compete for thecoupling groups of macrocyclic modules. In these variations, themacrocyclic module may couple as rapidly to another macrocyclic moduleas it does to the polymeric component, and may form a nanofilm in whichthe degree of coupling between the macrocyclic modules themselves iscomparable to that between the macrocyclic modules and the polymericcomponent. In other variations, the degree of coupling between themacrocyclic modules and the polymeric component may exceed that betweenthe macrocyclic modules themselves.

[0163] A nanofilm may be prepared by various methods where themacrocyclic modules couple directly to a polymeric component. Forexample, as shown in Table 7, the macrocyclic modules and polymericcomponent may be dissolved in organic solvent and coupled togetherbefore preparation of a nanofilm. This scheme may result in asubstantially single continuous phase within the nanofilm. In anothervariation shown in Table 7, the macrocyclic modules may be coupled tothe polymeric component during or after preparation of the nanofilmlayer.

[0164] In another aspect, a nanofilm of this invention may be formedfrom macrocyclic modules having functional groups which may coupledirectly to complementary fuinctional groups of a polymeric component.In these variations, the macrocyclic modules may not readily couple toother macrocyclic modules. Schemes for the preparation of such nanofilmsare illustrated in Table 8. TABLE 8 Schemes to prepare nanoflim frommacrocyclic modules which couple to polymeric components Reagents Schememacrocyclic module polymer

macrocyclic module amphiphilic polymer

[0165] Referring to Table 8, in some schemes the multicomponent mixtureof macrocyclic modules may include a polymer, or an amphiphilic polymer,or mixtures thereof. In these schemes, the macrocyclic modules directlycouple to polymeric components, but may not readily couple to othermodules.

[0166] In general, for a nanofilm prepared from macrocyclic moduleswhich directly couple to polymeric components, a discrete product isformed from the coupling of macrocyclic modules to a polymericcomponent. The discrete module-polymer product may be similar inmolecular architecture to a side-group branched polymer, or a graftpolymer. The discrete product may have a predominantly single continuousphase.

[0167] In one example in Table 8, secondary amine linkages betweensynthons of a macrocyclic module may couple to a carboxylic acid sidegroup of a copolymer such as the diacid form of poly(ethylene-co-maleicanhydride). In these schemes, macrocyclic modules couple to polymericcomponents, and both may be miscible in water. The coupling between themacrocyclic module and the polymeric component may also be indirect, andinvolve a linker molecule.

[0168] In the schemes illustrated in Table 8, multicomponent mixtures ofmacrocyclic modules used to prepare nanofilm may also includeamphiphilic molecules which may have a functional group that can coupleto macrocyclic modules or to polymeric components.

[0169] Nanofilms of Amphiphiles and Polymeric Components

[0170] In one aspect, this invention relates to the introduction ofpolymeric components into nanofilms comprising amphiphiles. Varioustypes of coupling may be used to prepare a nanofilm comprisingamphiphiles and polymeric components.

[0171] In some variations, an amphiphile may contain a polymerizablefunctional group, such as an acrylate group. In these variations, apolymeric component of a nanofilm may be formed in-situ with thenanofilm by using a multicomponent mixture which includes apolymerizable amphiphile, and which may also optionally include apolymerizable monomer.

[0172] In other variations, an amphiphilic molecule which does not havea polymerizable functional group may be used. In these variations,amphiphiles may be mixed with polymer, amphiphilic polymer,polymerizable monomer, polymerization amphiphile, or mixtures thereof toform a nanofilm having polymeric components.

[0173] In forming a nanofilm from multicomponent mixtures ofamphiphiles, the phase and domain behavior of the mixture may influencethe composition and properties of the nanofilm. Various schemes for thepreparation of nanofilms with polymeric components and amphiphiles areillustrated in Table 9. TABLE 9 Schemes to prepare nanofilm withamphiphiles Reagents Scheme polymerizable amphiphile polymer

polymerizable amphiphile amphiphilic polymer

polymerizable amphiphile polymerizable monomer

polymerizable amphiphile polymer amphiphilic polymer

polymerizable amphiphile amphiphilic polymer polymerizable monomer

amphiphile polymerizable amphiphile

amphiphile polymer polymerizable amphiphile

amphiphile amphiphilic polymer polymerizable amphilphile

amphiphile polymerizable monomer polymerizable amphiphile

polymer amphiphile

amphiphilic polymer amphiphile

amphiphile polymerizable monomer

[0174] Referring to Table 9, in some schemes a nanofilm is prepared withpolymerizable amphiphiles. In forming a nanofilm from polymerizableamphiphiles, a polymeric component may be formed in-situ from thepolymerizable amphiphiles. The mixtures used to fonn such nanofilms mayfurther include a polymer, or an amphiphilic polymer, a polymerizablemonomer, an amphiphile, or mixtures thereof.

[0175] In some schemes illustrated in Table 9, a nanofilm may beprepared from a polymer, an amphiphilic polymer, or a polymerizablemonomer. The nanofilms may optionally include an amphiphile.

[0176] Nanofilms of Polymieric Components

[0177] In one aspect, this invention relates variously to nanofilmsprepared from polymeric components. The polymeric components may bedirectly linked to each other, or may be linked via linker molecules.

[0178] In a non-limiting example, a LB film of PGM may be crosslinkedwith ethylene diamine to form a nanofllm. In another example, a LB filmof polyethylene imine (PEI) may be crosslinked with diethylene glycoldiglycidyl ether:

[0179] to form a nanofilm. Other possible combinations of the polymericcomponents included herein with appropriate linkers will be apparent tothose of skill in the art.

[0180] Nanoflim Composition and Characteristics

[0181] The characteristics of a nanofilm having one or more polymericcomponents may be substantially different than those of nanofilmprepared from macrocyclic modules alone. A nanofilm having polymericcomponents may be advantageously flexible and pliable compared tonanofilm prepared from modules alone, making it easier to fabricatearticles such as membranes for filtration and other separationprocesses. Various domains of a nanofilm having polymeric components mayundergo plastic deformation in response to stress, while other regionsmay be elastomeric. Nanofilms having polymeric components may bedeposited on a substrate to form a continuous, substantially unbrokensupported nanofilm or membrane.

[0182] Because the physical, chemical, and physico-chemical propertiesof nanofilm having one or more polymeric components may be dependent, inpart, on the fraction of polymeric component relative to macrocyclicmodules or other components, these properties can be varied by changingthe fraction of polymeric component in the nanofilm.

[0183] In general, components which are polymerizable may be used toprepare a polymeric component of a nanofilm in-situ during formation ofthe nanofilm. In-situ formation of a nanofilm polymeric componentprovides an alternative scheme in which phase and domain behavior of themulticomponent mixture may be modified. Schemes involving polymerizablespecies in a multicomponent mixture may be used to prepare, among othercompositions, nanofilm having smaller domains of phase separatedpolymeric components as compared to nanofilm prepared with polymer oramphiphilic polymer components alone. Multicomponent mixtures involvinga polymerizable amphiphile may be used to prepare nanofilm with feweropenings of micrometer dimension through which transport of species canoccur, as compared to nanofilm prepared with polymer or amphiphilicpolymer components alone.

[0184] In further variations of a nanofilm having one or more polymericcomponents, the polymeric molecules may not be coupled to othercomponents of the nanofilm. The ability of a polymeric component to makea nanofilm flexible or pliable may not require coupling to macrocyclicmodules or other components.

[0185] The area fraction of a component of a nanofilm is the fraction ofthe total nanofilm area that the individual component represents. Thenanofilm area fraction of a component is calculated from the molefraction (Mf) of the component in the initial mixture of components usedto form the nanofilm, and the mean molecular area (MMA) of the componentobtained by extrapolation of the high-surface pressure region of thepressure-area Langmuir isotherm of the pure component to zero surfacepressure. The area fraction of a component in the nanofilm is theproduct (Mf)(MMA) for the component, divided by the sum of the products(Mf)(MMA) for all components: areafraction=(Mf₁)(MMA₁)/[(Mf)₁(MMA)₁+(Mf)₂(MMA)₂+ . . . (Mf)_(n)(MMA)_(n)],where n is the number of components.

[0186] In general, area fraction can be measured where all nanofilmcomponents are immiscible in water or are amphiphilic, and all nanofilmcomponents are found in the initial mixture of components. Theuncertainty in measurement of area fraction may be up to about 20%,which includes uncertainty due to extrapolation of Langmuir isotherms,and for polymeric components which are polymers in the initial mixtureof components, uncertainty due to molecular weight polydispersity of thepolymer.

[0187] In some variations, the nanofilm area fraction of a component maynot always be measured by the above formula. For example, the areafraction of a component which was not in the initial mixture ofcomponents used to form the nanofilm, but entered the nanofilm later,would not be measured by the formula above. The area fraction of acomponent may also not be measured by the formula above when thecomponent does not form a stable Langmuir film for which MMA can bemeasured, or when a polymerizable component is used in the initialmixture which may have an MMA different from the polymer it produces.

[0188] A nanofilm may have any area fraction of polymeric components. Insome variations, a nanofilm may have an area fraction of polymericcomponents from about 0.005 (0.5%) to about 0.98 (98%). In othervariations, a nanofilm may have an area fraction of polymeric componentsfrom about 0.005 to about 0.7, often from about 0.005 to about 0.5,sometimes from about 0.005 to about 0.3, sometimes from about 0.005 toabout 0.2, sometimes from about 0.005 to about 0.1, sometimes from about0.005 to about 0.05, sometimes from about 0.005 to about 0.02, sometimesfrom about 0.50 to about 0.98.

[0189] A nanofilm may have an area fraction or weight percent ofpolymeric components sufficient to make it flexible and pliable so thatit may be deposited on a substrate as a homogeneous film with littlemechanical breakage, or to reduce the surface modulus of the nanofilm.Flexibility of a nanofilm having polymeric components may bedemonstrated by depositing the nanofilm on various substrates to form acontinuous, substantially unbroken film on the substrate, or by reducingsurface modulus of the nanofilm.

[0190] A nanofilm may have any molar ratio of polymeric components, asmeasured against the other components. In some variations, the molarratio of polymeric components may be, for example, about 0.005 to about0.995, for example about 0.010 to about 0.990, for example, about 0.01to about 0.50, for example about 0.01 to about 0.20, for example, about0.20 to about 0.50, for example about 0.50 to about 0.99, for example,about 0.1 to about 0.9, as measured against the other components. Incertain embodiments, the molar ratio of polymeric component: module isabout 0.1:0.9, about 0.2:0.8, about 0.5:0.5, about 0.25:0.75, or about0.90:0.10.

[0191] The thickness of nanofilms described herein, whether throughcoupled or non coupled components, is exceptionally small, often beingless than about 30 nanometers, sometimes less than about 20 nanometers,and sometimes from about 1-15 nanometers. The thickness of a nanofilmdepends partly on the structure and nature of the groups on the modulesor other species which impart amphiphilic character to the modules, andpartly on the nature of the polymeric or other components. The thicknessmay be dependent on temperature, and the presence of solvent on thesurface or located within the nanofilm. The thickness may be modified ifthe groups on the modules or other components which impart amphiphiliccharacter, in particular the lipophilic moiety, to the component areremoved or modified after the components have been coupled, or at otherpoints during or after the process of preparation of a nanofilm. Thethickness of a nanofilm may also depend on the structure and nature ofthe surface attachment groups on the components. The thickness ofnanofilms may be less than about 300, 250, 200, 150, 100, 90, 80, 70,60, 50, 40, 30, 20, 10 or 5 Å.

[0192] The nanofilm composition may include uniquely structured regionsin which modules and/or other components are coupled. Coupling ofmodules and/or other components provides a nanofilm in which uniquestructures may be formed. Nanofilm structures define pores through whichatoms, molecules, or particles of only up to a certain size andcomposition may pass. One variation of a nanofilm structure includes anarea of nanofilm able to face a fluid medium, either liquid or gaseous,and provide pores or openings through which atoms, ions, smallmolecules, biomolecules, or other species are able to pass. Thedimensions of the pores defined by nanofilm structures may beexemplified by quantum mechanical calculations and evaluations, andphysical tests, as further described in the following Examples.

[0193] The dimensions of the pores defined by nanofilm structures aredescribed by actual atomic and chemical structural features of thenanofilm. The approximate diameters of pores formed in the structure ofa nanofilm are from about 1-150 Å, or more. In some embodiments, thedimensions of the pores are about 1-10 Å, about 3-15 Å, about 10-15 Å,about 15-20 Å, about 20-30 Å, about 30-40 Å, about 40-50 Å, about 50-75Å, about 75-100 Å, about 100-125 Å, about 125-150 Å, about 150-300 Å,about 600-1000 Å. The approximate dimensions of pores formed in thestructure of a nanofilm are useful to understand the porosity of thenanofilm. On the other hand, the porosity of conventional membranes isnormally quantified by empirical results such as molecular weightcut-off, which reflects complex diffusive and other transportcharacteristics.

[0194] In one variation, a nanofilm structure may comprise an array ofcoupled modules which provides an array of pores of substantiallyuniform size. The pores of uniform size may be defined by the individualmodules themselves. Each module defines a pore of a particular size,depending on the conformation and state of the module. For example, theconformation of the coupled module of the nanofilm may be different fromthe nascent, pure macrocyclic module in a solvent, and both may bedifferent from the conformation of the amphiphilic module oriented on asurface before coupling. A nanofilm structure including an array ofcoupled modules can provide a matrix or lattice of pores ofsubstantially uniform dimension based on the structure and conformationof the coupled modules.

[0195] Modules of various composition and structure may be preparedwhich define pores of different sizes. A nanofilm prepared from coupledmodules may be made from any one of a variety of modules. Thus,nanofilms having pores of various dimensions are provided, depending onthe particular module used to prepare the nanofilm.

[0196] In other instances, nanofilm structures define pores in thematrix of coupled modules or other components. Pores defined by nanofilmstructures may have a wide range of dimensions, for example, dimensionscapable of selectively blocking the passage of small molecules or largemolecules. For example, nanofilm structures may be formed from thecoupling of two or more modules, in which an interstitial pore isdefined by the combined structure of the linked modules. A nanofilm mayhave an extended matrix of pores of various dimensions andcharacteristics. Interstitial pores may be, for example, less than about5 Å, less than about 10 Å, about 3-15 Å, about 10-15 Å, about 15-20 Å,about 20-30 Å, about 30-40 Å, about 40-50 Å, about 50-75 Å, about 75-100Å, about 100-125 Å, about 125-150 Å, about 150-300 Å, about 300-600 Å,about 600-1000 Å. In some variations, the other components may act as a“filler” to limit the porosity of the nanofilm. In other variations, theother components will provide porosity to the nanofilm, depending on thetype and extent of cross-linking between the components.

[0197] The coupling process may result in a nanofilm in which regions ofthe nanofilm are not precisely monomolecular layers. Various types oflocal structures are possible which do not prevent use of the nanofilmin a variety of applications. Local structural features may includeamphiphilic components or species, including polymeric species, whichare flipped over relative to their neighbors, or turned in a differentorientation, having their hydrophobic and hydrophilic facets orienteddifferently than neighboring species. Local structural features may alsoinclude overlaying or stacking of molecules in which the nanofilm is twoor more molecular layers thick, local regions in which the interlinkingof the modules or other components is not complete so that some of theavailable coupling groups are not coupled to other species, or localregions in which there is an absence of a particular molecule orcomponent. Other local structural features may include grain boundariesand orientational faults. In one variation, the nanofilm has a thicknessof up to 30 nanometers due to the layering of nanofilm structures.

[0198] The nanofilms disclosed herein may be substantially uniform withrespect to the orientation of their amphiphilic components, but may insome embodiments comprise regions of local structural features asindicated hereinabove. Local structural features may comprise, forexample, greater than about 30%, less than about 30%, less than about20%, less than about 15%, less than about 10%, less than about 5%, lessthan about 3%, less than about 1% of the surface area of the nanofilm.

[0199] Phase and Domain Behavior of Nanofilm

[0200] In some variations of a nanofilm having one or more polymericcomponents, the nanofilm may have domains in which a polymeric componentor components are intermixed at the atomic level with macrocyclicmodules or other species, and solubilized with each other. In thesevariations, the macrocyclic modules or other species may be misciblewith the polymeric component.

[0201] In other variations of a nanofilm having one or more polymericcomponents, the polymeric molecules, macrocyclic modules, or othercomponents may be located in finite-sized aggregates. Above somecritical concentration in a particular solvent, polymeric molecules,macrocyclic modules, or other components may collect into finite-sizedaggregates. These finite-sized aggregates may persist at the air-waterinterface in formation of a nanofilm. The structure of the aggregatesmay be affected by the geometry and shape of the molecules, among otherfactors, or the capability of the molecules to couple in particularorientations with other species. The structure of the aggregates may behighly dynamic with motion and exchange of the molecules at variousrates. In these variations, the self assembled aggregates of one speciesmay be interspersed in a continuous phase of another species, where theother species is not aggregated. Different molecules or components mayform separate aggregates, or be combined in an aggregate structure.Coupling between macrocyclic modules or other components and thepolymeric molecules may occur at a surface, edge, or point of the selfassembled aggregates.

[0202] In further variations of a nanofilm having one or more polymericcomponents, the polymeric molecules may reside in domains that aresubstantially polymeric, which may be interspersed with domains composedsubstantially of other species. In these variations, a polymericcomponent may be immiscible or phase separated from macrocyclic modulesor other components. Phase separation may occur when the aggregation ofpolymeric molecules is not limited to a small finite size, but maycontinue until regions of polymeric molecules are separated from regionsof other molecules. The form of a polymeric component in thesevariations may be a solid, gel, or liquid-like polymer melt, or anamorphous composition, in the form of layers, beads, discs or mixturesthereof, and can be homogeneous or heterogeneous in structure orcomposition. Polymeric components of such nanofilms may form hard andsoft domains typical of thermoplastic elastomers, or a polymericcomponent may form a soft domain relative to a hard domain ofmacrocyclic modules. A polymeric component may form regions which areamorphous, glassy, semicrystalline, or crystalline, or have subregionswith those characteristics. A region of a polymeric component mayexhibit rubberlike elasticity or viscoelastic states. Differentpolymeric components may form separate phases, or may be miscible witheach other while remaining immiscible with macrocyclic modules or othercomponents. Coupling between macrocyclic modules or other components andpolymeric molecules may occur at or near the interface between thephases, and may contribute to adhesion of the phases.

[0203] A nanofilm may also be prepared with mixtures of differentmacrocyclic modules, or with mixtures of macrocyclic modules, polymericcomponents, and other species. A nanofilm may have an array of coupledmodules and other species in which the positional ordering of themodules and other species is random, or is non-random with regions inwhich one type of species is predominant. In these variations, thepolymeric component maybe intermixed, aggregated, or phase separatedfrom the macrocyclic modules and other species, as described above.Nanofilms made from mixtures of different modules, or with mixtures ofmacrocyclic modules and other amphiphilic molecules may also haveinterspersed arrays of pores of various sizes.

[0204] Methods of Preparing Nanofilms

[0205] In Langmuir film methods, a monolayer of oriented amphiphilicspecies, for example amphiphilic modules, amphiphilic polymers, and/oramphiphiles, is formed on the surface of a liquid subphase. In oneexample, the amphiphilic components may be dissolved in a solvent anddeposited on an air-subphase interface in a Langmuir trough to form themonolayer. Typically, movable plates or barriers are used to compressthe monolayer and decrease its surface area to form a more densemonolayer. At various degrees of compression, having correspondingsurface pressures, the monolayer may reach various condensed states.Surfaces which may be used to orient amphiphiles include interfaces suchas gas-liquid, air-water, immiscible liquid-liquid, liquid-solid, orgas-solid interfaces. The thickness of the oriented layer may besubstantially a monomolecular layer thickness.

[0206] Surface pressure versus film area isotherms are obtained by theWilhelmy balance method to monitor the state of the film. Extrapolationof the isotherm to zero surface pressure reveals the average surfacearea per component, or mean molecular area, before the components arecoupled. The isotherm gives an empirical indication of the state of thethin film. Surface-oriented macrocyclic modules and/or other componentsin a nanofilm layer may be in an expanded state, a liquid state, or aliquid-expanded state, or may be condensed, collapsed, or a solid phaseor closepacked state.

[0207] Nanofilms may be prepared by various alternative methods. Forexample, linker molecules may be added to the solution containing themodules and/or other components, which is subsequently deposited on thesurface of the Langmuir subphase. Alternatively, the linker moleculesmay be added to the water subphase of the Langmuir trough, andsubsequently transfer to the layer phase containing macrocyclic moduleand/or other components for coupling.

[0208] In one variation of this invention, a water-soluble polymericcomponent may be added to the subphase of a Langmuir trough. In othervariations, a polymeric component may be dissolved in water or solventand spread on an interface. One or more polymeric components may beco-spread on an interface with macrocyclic modules, and optionally withlinker molecules. In other variations, one or more polymeric componentsmay be co-spread on an interface with macrocyclic modules and/or linkermolecules, and/or other amphiphilic molecules.

[0209] In some instances, macrocyclic modules and/or other componentsmay be added to the subphase of the Langmuir trough, and subsequentlytransfer to the interface.

[0210] Other variations will be apparent to those of skill in the art.

[0211] In general, coupling of the components of a nanofilm may beinitiated by chemical, thermal, photochemical, electrochemical, andirradiative methods. In some variations of this invention, the type ofcoupling of the components of a nanofilm may depend on the type ofinitiation and the chemical process involved. For example, in forming ananofilm from a multicomponent mixture, species in the mixture which arepolymerizable may produce polymeric components by non-selective chain oraddition polymerization. The type of the coupling of macrocyclic modulesto polymerizable species or polymeric components depends on thefunctional groups of the modules. For example, free radicalpolymerization of unsaturated polymeric components, amphiphiles, ormonomers may couple polymeric components to benzene synthons ofmacrocyclic modules, or to other reactive or unsaturated sites.

[0212] Functional groups added to the modules or other components toimpart amphiphilic character may in some embodiments be removed duringor after formation of the nanofilm. In one embodiment, groups whichimpart amphiphilic character to a polymeric component may be removedafter formation of the nanofilm. In another embodiment, groups whichimpart amphiphilic character to macrocyclic modules may be removed afterformation of the nanofilm. The method of removal depends on thefunctional group. The groups attached to the modules which impartamphiphilic character to the component may include functional groupswhich can be used to remove the groups at some point during or after theprocess of formation of a nanofilm. Acid or base hydrolysis may be usedto remove groups attached to the component via a carboxylate or amidelinkage. An unsaturated group located in the functional group whichimparts amphiphilic character to the module may be oxidized and cleavedby hydrolysis. Photolytic cleavage of the functional group which impartsamphiphilic character to the module may also be done. Examples ofcleavable functional groups include

[0213] where n is zero to four, which is cleavable by light activation,and

[0214] where n is zero to four, and m is 7 to 27, which is cleavable byacid or base catalyzed hydrolysis.

[0215] Examples of functional groups added to the components to impartamphiphilic character to the modules include alkyl groups, alkoxygroups, —NHR, —OC(O)R, —C(O)OR, —NHC(O)R, —C(O)NHR, —CH═CHR, and —C≡CR,where the carbon atoms of an alkyl group may be interrupted by one ormore —S—, double bond, triple bond or —SiRR′— group(s), or substitutedwith one or more fluorine atoms, or any combination thereof, where R andR′ are independently hydrogen or alkyl.

[0216] In alternative variations, the multicomponent mixtures ofmacrocyclic modules and/or other components may include additives,dispersants, surfactants, excipients, compatiblizers, emulsifiers,suspension agents, plasticizers, or other species which modify theproperties of the components. For example, compatiblizers may be used toreduce domain sizes and form more continuous phase dispersion of thecomponents of a nanofilm.

[0217] In some instances, the nanofilm may be derivatized to providebiocompatability or reduce fouling of the nanofilm by attachment oradsorption of biomolecules.

[0218] Nanofilms may be deposited on a substrate by various methods,such as Langmuir-Schaefer, Langmuir-Blodgett, or other methods used withLangmuir systems. In one variation, a nanofilm is deposited on asubstrate in a Langmuir tank by locating the substrate in the subphasebeneath the air-water interface, and lowering the level of the subphaseuntil the nanofilm lands gently on the substrate and is thereforedeposited. A description of Langmuir films and substrates is given inU.S. Pat. Nos. 6,036,778, 4,722,856, 4,554,076, and 5,102,798, and in R.A. Hendel et al., Vol. 119, J. Am. Chem. Soc. 6909-18 (1997). Adescription of films on substrates is given in Munir Cheryan,Ultrafiltration and Microfiltration Handbook (1998). A description ofpolymers on surfaces is given in Jacob N. Israelachvili, Intermolecularand Surface Forces (1991).

[0219] Other methods to prepare a nanofilm having polymeric componentsinclude forced removal of solvent to prepare a film, such as spincoating methods and spray coating methods, as well as coating anddeposition methods including interfacial, dip coating, knife-edgecoating, grafting, casting, phase inversion, or electroplating or otherplating methods.

[0220] Nanofilms deposited on a substrate may be cured or annealed bychemical, thermal, photochemical, electrochemical, irradiative or dryingmethods during or after deposition on a substrate. For example, chemicalmethods include reactions with vapor phase reagents such asethylenediamine or solution phase reagents. A nanofilm treated by anymethod to attach or couple it to a substrate may be said to be cured.

[0221] The deposition may result in non-covalent or weak attachment ofthe nanofilm to the substrate through physical interactions and weakchemical forces such as van der Waals forces and weak hydrogen bonding.The nanofilm may in some embodiments be bound to the substrate throughionic or covalent interaction, or other type of interaction.

[0222] The substrate may be any surface of any material. Substrates maybe porous or non-porous, and may be made from polymeric and inorganicsubstances. Examples of porous substrates are plastics or polymers,track-etch polycarbonate, track-etch polyester, polyethersulfone,polysulfone, gels, hydrogels, cellulose acetate, polyamide, PVDF,polyethylene terephthalate or polybutylene terephthalate, polyvinylchloride, polyvinylidene chloride, polytetrafluoroethylene, polyethyleneor polypropylene, ceramics, anodic alumina, laser ablated and otherporous polyimides, and UV etched polyacrylate. Examples of non-poroussubstrates are silicon, germanium, glass, metals such as platinum,nickel, palladium, aluminum, chromium, niobium, tantalum, titanium,steel, or gold, glass, silicates, aluminosilicates, non-porous polymers,and mica. Further examples of substrates include diamond and indium tinoxide. Preferred substrates include silicon, gold, SiO₂,polyethersulfone, and track etch polycarbonate. In some embodiments, thesubstrate is SiO₂. In other embodiments, the substrate is polycarbonatetrack etch membrane.

[0223] Substrates may have any physical shape or form including films,sheets, plates, or cylinders, and may be particles of any shape or size.

[0224] A nanofilm deposited on a substrate may serve as a membrane. Anynumber of layers of nanofilm may be deposited on the substrate to form amembrane. In some variations, nanofilm is deposited on both sides of asubstrate.

[0225] A layer or layers of various spacing materials may be depositedor attached in between layers of a nanofilm, and a spacing layer mayalso be used in between the substrate and the first deposited layer ofnanofilm. Examples of spacing layer compositions include polymericcompositions, hydrogels (acrylates, poly vinyl alcohols, polyurethanes,silicones), thermoplastic polymers (polyolefins, polyacetals,polycarbonates, polyesters, cellulose esters), polymeric foams,thermosetting polymers, hyperbranched polymers, biodegradable polymerssuch as polylactides, liquid crystalline polymers, polymers made by atomtransfer radical polymerization (ATRP), polymers made by ring openingmetathesis polymerization (ROMP), polyisobutylenes and polyisobutylenestar polymers, and amphiphilic polymers. Other examples of spacing layercompositions include inorganics, such as inorganic particles such asinorganic microspheres, colloidal inorganics, inorganic minerals, silicaspheres or particles, silica sols or gels, clays or clay particles, andthe like. Examples of amphiphilic molecules include amphiphilescontaining polymerizable groups such as diynes, enes, or amino-esters.The spacing layers may serve to modify barrier properties of thenanofilm, or may serve to modify transport, flux, or flowcharacteristics of the membrane or nanofilm. Spacing layers may serve tomodify functional characteristics of the membrane or nanofilm, such asstrength, modulus, or other properties. In some variations, thepolymeric components of a nanofilm may provide a spacing layer betweenthe nanofilm and a substrate.

[0226] In some variations, a nanofilm having polymeric components may bedeposited on a surface and adhere to the surface to a degree sufficientfor many applications, such as filtration and membrane separations,without coupling to the surface. Nanofilm having polymeric componentsmay be advantageously cohesive to a substrate, which may include somecoupling interactions.

[0227] In other variations, a nanofilm may be coupled to a substratesurface. Surface attachment groups may be provided on a polymericcomponent of a nanofilm, which may be used to couple the nanofilm to thesubstrate. Coupling of some, but not all of the surface attachmentgroups may be done to attach the nanofilm to the substrate. Optionally,surface attachment groups may be provided on the macrocyclic modulesand/or other components of a nanofilm.

[0228] Examples of functional groups which may be used as surfaceattachment groups to couple a nanofilm to a substrate include aminegroups, carboxylic acid groups, carboxylic ester groups, alcohol groups,glycol groups, vinyl groups, styrene groups, epoxide groups, thiolgroups, magnesium halo or Grignard groups, acrylate groups, acrylamidegroups, diene groups, aldehyde groups, and mixtures thereof.

[0229] A substrate may have functional groups which couple to thefunctional groups of a nanofilm. The functional groups of the substratemay be surface groups or linking groups bound to the substrate, whichmay be formed by reactions which bind the surface groups or linkinggroups to the substrate. Surface groups may also be created on thesubstrate by a variety of treatments such as cold plasma treatment,surface etching methods, solid abrasion methods, or chemical treatments.Some methods of plasma treatment are given in Inagaki, Plasma SurfaceModification and Plasma Polymerization, Technomic, Lancaster, Pa., 1996.In some embodiments, the substrate is derivatized with APTES. In otherembodiments, the substrate is derivatized withmethylacryloxymethyltrimethoxysilane (MAOMTMOS). In other embodiments,the substrate is derivatized with acryloxypropyltrimethoxysilane(AOPTMOS).

[0230] Surface attachment groups of the nanofilm and the surface may beblocked with protecting groups until needed. Non-limiting examples ofsuitable functional groups for coupling the nanofilm to the substrateand the resulting linkages may be found in Tables 2 and 4. Thefunctional groups on the nanoflim may be from any component of thenanofilm, for example, the macrocyclic modules, the polymer component,or the amphiphilic component.

[0231] Surface attachment groups may be connected to a nanofilm byspacer groups. Likewise, substrate functional groups may be connected tothe substrate by spacer groups. Spacer groups for surface attachmentgroups may be polymeric. Examples of polymeric spacers includepolyethylene oxides, polypropylene oxides, polysaccharides, polylysines,polypeptides, poly(amino acids), polyvinylpyrrolidones, polyesters,polyvinylchlorides, polyvinylidene fluorides, polyvinylalcohols,polyurethanes, polyamides, polyimides, polysulfones, polyethersulfones,polysulfonamides, and polysulfoxides. Examples of polymeric spacerstructures include linear, branched, comb and dendrimeric polymers,random and block copolymers, homo- and heteropolymers, flexible andrigid chains. Spacer groups for surface attachment groups may alsoinclude bifunctional linker groups or heterobifunctional linker groupsused to couple biomolecules and other chemical species.

[0232] In one variation, a photoreactive group such as a benzophenone isbound to the substrate. The photoreactive group may be activated withlight, for example, ultraviolet light, to provide a reactive specieswhich couples to a nanofilm. The photoreactive species may couple to anyatom or group of atoms of the nanofilm.

[0233] Surface attachment of modules may also be achieved throughligand-receptor mediated interactions, such as biotin-streptavidin. Forexample, the substrate may be coated with streptavidin, and biotin maybe attached to the modules, for example, through linker groups such asPEG or alkyl groups.

[0234] Memnbranes and Filtration Function

[0235] The nanofilms described herein may be useful, for example, asmembranes. The membrane may be brought into contact with a fluid orsolution, separating a species or component from that fluid or solution,for example, for purposes of filtration. Normally, a membrane is asubstance which acts as a barrier to block the passage of some species,while allowing restricted or regulated passage of other species. Ingeneral, permeants may traverse the membrane if they are smaller than acut-off size, or have a molecular weight smaller than a so-calledcut-off molecular weight. The membrane may be called impermeable tospecies which are larger than the cut-off molecular weight. The cut-offsize or molecular weight is a characteristic property of the membrane.Selective permeation is the ability of the membrane to cut-off,restrict, or regulate passage of some species, while allowing smallerspecies to pass. Thus, the selective permeation of a membrane may bedescribed functionally in terms of the largest species able to pass themembrane under given conditions. The size or molecular weight of variousspecies may also be dependent on the conditions in the fluid to beseparated, which may determine the form of the species. For example,species may have a sphere of hydration or solvation in a fluid, and thesize of the species in relation to membrane applications may or may notinclude the water of hydration or the solvent molecules. Thus, amembrane is permeable to a species of a fluid if the species cantraverse the membrane in the form in which it normally would be found inthe fluid. Permeation and permeability may be affected by interactionbetween the species of a fluid and the membrane itself. While varioustheories may describe these interactions, the empirical measurement ofpass/no-pass information relating to a nanofilm, membrane, or module isa useful tool to describe permeation properties. A membrane isimpermeable to a species if the species cannot pass through themembrane.

[0236] Pores may be provided in the nanofilms described herein, forexample, pores may be supplied in the structure of the nanofilm. Poresmay be supplied in the structure of the macrocyclic modules. Pores mayin some cases be supplied from the packing of the macrocyclic modulesand the polymeric components. The type and degree of crosslinkingbetween components may influence pore size. The nanofilms describedherein comprising one or more polymeric components may advantageouslyhave reduced numbers of micrometer-sized or macroscopic openings whichaffect use in filtration and selective permeation.

[0237] The nanofilms may have molecular weight species cut offs of, forexample, greater than about 15 kDa, greater than about 10 kDa, greaterthan about 5 kDa, greater that about 1 kDa, greater than about 800 Da,greater than about 600 Da, greater than about 400 Da, greater than about200 Da, greater than about 100 Da, greater than about 50 Da, greaterthan about 20 Da, less than about 15 kDa, less than about 10 kDa, lessthan about 5 kDa, less that about 1 kDa, less than about 800 Da, lessthan about 600 Da, less than about 400 Da, less than about 200 Da, lessthan about 100 Da, less than about 50 Da, less than about 20 Da, about13 kDa, about 190 Da, about 100 Da, about 45 Da, about 20 Da.

[0238] “High permeability” indicates a clearance of, for example,greater than about 70%, greater than about 80%, greater than about 90%of the solute. “Medium permeability” indicates a clearance of, forexample, less than about 50%, less than about 60%, less than about 70%of the solute. “Low permeability” indicates a clearance of less than,for example, about 10%, less than about 20%, less than about 30% of thesolute. A membrane is impermeable to a species if it has a very lowclearance (for example, less than about 5%, less than about 3%) for thespecies, or if it has very high rejection for the species (for example,greater than about 95%, greater than about 98%). The passage orexclusion of a solute is measured by its clearance, which reflects theportion of solute that actually passes through the membrane. Forexample, the no pass symbol in Tables 16-17 indicates that the solute ispartly excluded by the module, sometimes less than 90% rejection, oftenat least 90% rejection, sometimes at least 98% rejection. The passsymbol indicates that the solute is partly cleared by the module,sometimes less than 90% clearance, often at least 90% clearance,sometimes at least 98% clearance.

[0239] Examples of processes in which nanofilms may be useful includeprocesses involving liquid or gas as a continuous fluid phase,filtration, clarification, fractionation, pervaporation, reverseosmosis, dialysis, hemodialysis, affinity separation, oxygenation, andother processes. Filtration applications may include ion separation,desalinization, gas separation, small molecule separation, separation ofenantiomers, ultrafiltration, microfiltration, hyperfiltration, waterpurification, sewage treatment, removal of toxins, removal of biologicalspecies such as bacteria, viruses, or fungus.

[0240] Synthons and Macrocyclic Modules

[0241] Synthons

[0242] As used herein, the term “synthon” refers to a molecule used tomake a macrocyclic module. A synthon may be substantially one isomericconfiguration, for example, a single enantiomer. A synthon may besubstituted with functional groups which are used to couple a synthon toanother synthon or synthons, and which are part of the synthon. Asynthon may be substituted with an atom or group of atoms which are usedto impart hydrophilic, lipophilic, or amphiphilic character to thesynthon or to species made from the synthon. The synthon before beingsubstituted with functional groups or groups used to impart hydrophilic,lipophilic, or amphiphilic character may be called the core synthon. Asused herein, the term “synthon” refers to a core synthon, and alsorefers to a synthon substituted with functional groups or groups used toimpart hydrophilic, lipophilic, or amphiphilic character.

[0243] As used herein, the term “cyclic synthon” refers to a synthonhaving one or more ring structures. Examples of ring structures includearyl, heteroaryl, and cyclic hydrocarbon structures including bicyclicring structures and multicyclic ring structures. Examples of core cyclicsynthons include, but are not limited to, benzene, cyclohexadiene,cyclopentadiene, naphthalene, anthracene, phenylene, phenanthracene,pyrene, triphenylene, phenanthrene, pyridine, pyrimidine, pyridazine,biphenyl, bipyridyl, cyclohexane, cyclohexene, decalin, piperidine,pyrrolidine, morpholine, piperazine, pyrazolidine, quinuclidine,tetrahydropyran, dioxane, tetrahydrothiophene, tetrahydrofuran, pyrrole,cyclopentane, cyclopentene, triptycene, adamantane,bicyclo[2.2.1]heptane, bicyclo[2.2.1]heptene, bicyclo[2.2.2]octane,bicyclo[2.2.2]octene, bicyclo[3.3.0]octane, bicyclo[3.3.0]octene,bicyclo[3.3.1]nonane, bicyclo[3.3.1]nonene, bicyclo[3.2.2]nonane,bicyclo[3.2.2]nonene, bicyclo[4.2.2]decane, 7-azabicyclo[2.2.1]heptane,1,3-diazabicyclo[2.2.1]heptane, and spiro[4.4]nonane. A core synthoncomprises all isomers or arrangements of coupling the core synthon toother synthons. For example, the core synthon benzene includes synthonssuch as 1,2- and 1,3-substituted benzenes, where the linkages betweensynthons are formed at the 1,2- and 1,3-positions of the benzene ring,respectively. For example, the core synthon benzene includes1,3-substituted synthons such as

[0244] where L is a linkage between synthons and the 2,4,5,6 positionsof the benzene ring may also have substituents. A condensed linkagebetween synthons involves a direct coupling between a ring atom of onecyclic synthon to a ring atom of another cyclic synthon, for example,where synthons M—X and M—X couple to form M—M, where M is a cyclicsynthon and X is halogen; as for example when M is phenyl resulting inthe condensed linkage

[0245] Macrocyclic Modules

[0246] A macrocyclic module is a closed ring of coupled synthons. Tomake a macrocyclic module, synthons may be substituted with functionalgroups to couple the synthons to form a macrocyclic module. Synthons mayalso be substituted with functional groups which will remain in thestructure of the macrocyclic module. Functional groups which remain inthe macrocyclic module may be used to couple the macrocyclic module toother macrocyclic modules or other components.

[0247] A macrocyclic module may contain from three to about twenty-fourcyclic synthons. In the closed ring of a macrocyclic module, a firstcyclic synthon may be coupled to a second cyclic synthon, the secondcyclic synthon may be coupled to a third cyclic synthon, the thirdcyclic synthon may be coupled to a fourth cyclic synthon, if four cyclicsynthons are present in the macrocyclic module, the fourth to a fifth,and so on, until an nth cyclic synthon may be coupled to itspredecessor, and the nth cyclic synthon may be coupled to the firstcyclic synthon to form a closed ring of cyclic synthons. In onevariation, the closed ring of the macrocyclic module may be formed witha linker molecule.

[0248] A macrocyclic module may be an amphiphilic macrocyclic modulewhen hydrophilic and lipophilic functional groups exist in thestructure. The amphiphilic character of a macrocyclic module may arisefrom atoms in the synthons, in the linkages between synthons, or infunctional groups coupled to the synthons or linkages.

[0249] In some variations, one or more of the synthons of a macrocyclicmodule may be substituted with one or more lipophilic moieties, whileone or more of the synthons may be substituted with one or morehydrophilic moieties, thereby forming an amphiphilic macrocyclic module.Lipophilic and hydrophilic moieties may be coupled to the same synthonor linkage in an amphiphilic macrocyclic module. Lipophilic andhydrophilic moieties may be coupled to the macrocyclic module before orafter formation of the closed ring of the macrocyclic module. Forexample, lipophilic or hydrophilic moieties may be added to themacrocyclic module after formation of the closed ring by substitution ofa synthon or linkage.

[0250] The amphiphilicity of a macrocyclic module may be characterizedin part by its ability to form a stable Langmuir film. A Langmuir filmmay be formed on a Langmuir trough at a particular surface pressuremeasured in milliNewtons per meter (mN/m) with a particular barrierspeed measured in millimeters per minute (mm/min), and the isobariccreep or change in film area at constant surface pressure can bemeasured to characterize stability of the film. For example, a stableLangmuir film of macrocyclic modules on a water subphase may have anisobaric creep at 5-15 mN/m such that the majority of the film area isretained over a period of time of about one hour. Examples of stableLangmuir films of macrocyclic modules on a water subphase may haveisobaric creep at 5-15 mN/m such that about 70% of the film area isretained over a period of time of about 30 minutes, sometimes about 70%of the film area is retained over a period of time of about 40 minutes,sometimes about 70% of the film area is retained over a period of timeof about 60 minutes, and sometimes about 70% of the film area isretained over a period of time of about 120 minutes. Other examples ofstable Langmuir films of macrocyclic modules on a water subphase mayhave isobaric creep at 5-15 mN/m such that about 80% of the film area isretained over a period of time of about thirty minutes, sometimes about85% of the film area is retained over a period of time of about thirtyminutes, sometimes about 90% of the film area is retained over a periodof time of about thirty minutes, sometimes about 95% of the film area isretained over a period of time of about thirty minutes, and sometimesabout 98% of the film area is retained over a period of time of aboutthirty minutes.

[0251] In one aspect, an individual macrocyclic module may include apore in its structure. Each macrocyclic module may define a pore of aparticular size, depending on the conformation and state of the module.Various macrocyclic modules may be prepared which define pores ofdifferent sizes.

[0252] A macrocyclic module may have flexibility in its structure.Flexibility may permit a macrocyclic module to more easily form linkageswith other macrocyclic modules and/or other components by couplingreactions. Flexibility of a macrocyclic module may also play a role inregulating passage of species through the pore of the macrocyclicmodule. For example, flexibility may affect the dimension of the pore ofan individual macrocyclic module since various conformations may beavailable to the structure. For example, the macrocyclic module may havea certain pore dimension. in one conformation when no substituents arelocated at the pore, and the same macrocyclic module may have adifferent pore dimension in another conformnation when one or moresubstituents of that macrocycle are located at the pore. Likewise, amacrocyclic module may have a certain pore dimension in one conformationwhen one group of substituents are located at the pore, and have adifferent pore dimension in a different conformation when a differentgroup of substituents are located at the pore. For example, the “onegroup” of substituents located at the pore may be three alkoxy groupsarranged in one regioisomer, while the “different group” of substituentsmay be two alkoxy groups arranged in another regioisomer. The effect ofthe “one group” of substituents located at the pore and the “differentgroup” of substituents located at the pore is to provide a macrocyclicmodule composition which may regulate transport and filtration, inconjunction with other regulating factors.

[0253] In making macrocyclic modules from synthons, the synthons may beused as a substantially pure single isomer, for example, as a puresingle enantiomer.

[0254] In making macrocyclic modules from synthons, one or more couplinglinkages are formed between adjacent synthons. The linkage formedbetween synthons may be the product of the coupling of one functionalgroup on one synthon to a complementary functional group on a secondsynthon. For example, a hydroxyl group of a first synthon may couplewith an acid group or acid halide group of a second synthon to form anester linkage between the two synthons. Another example is an iminelinkage, —CH═N—, resulting from the reaction of an aldehyde, —CH═O, onone synthon with an amine, —NH₂, on another synthon. Examples ofsuitable complementary functional groups and linkages between synthonsare shown in Table 2, wherein “synthon” may substitute for “module”.

[0255] The functional groups of synthons used to form linkages betweensynthons or other macrocyclic modules may be separated from the synthonby a spacer. A spacer can be any atom or group of atoms which couplesthe functional group to the synthon, and does not interfere with thelinkage-formning reaction. A spacer is part of the functional group, andbecomes part of the linkage between synthons. An example of a spacer isa methylene group, —CH₂—. The spacer may be said to extend the linkagebetween synthons. For example, if one methylene spacer were inserted inan imine linkage, —CH═N—, the resulting imine linkage may be —CH₂CH═N—.

[0256] A linkage between synthons may also contain one or more atomsprovided by an external moiety other than the two functional groups ofthe synthons. An external moiety may be a linker molecule which maycouple with the functional group of one synthon to form an intermediatewhich couples with a finctional group on another synthon to form alinkage between the synthons, such as, for example, to form a closedring of synthons from a series of coupled synthons. An example of alinker molecule is formaldehyde. For example, amino groups on twosynthons may undergo Mannich reaction in the presence of formaldehyde asthe linker molecule to produce the linkage —NHCH₂NH—. Examples ofsuitable functional groups and linker molecules are shown in Table 4,wherein “synthon” may substitute for “module.”

[0257] A macrocyclic module may include functional groups for couplingthe macrocyclic module to a solid surface, substrate, or support.Examples of functional groups of macrocyclic modules which can be usedto couple to a substrate or surface include amine, carboxylic acid,carboxylic ester, benzophenone and other light activated crosslinkers,alcohol, glycol, vinyl, styryl, olefin styryl, epoxide, thiol, magnesiumhalo or Grignard, acrylate, acrylamide, diene, aldehyde, and mixturesthereof. These functional groups may be coupled to the closed ring ofthe macrocyclic module, and may optionally be attached by a spacergroup. Examples of solid surfaces include metal surfaces, ceramicsurfaces, polymer surfaces, semiconductor surfaces, silicon wafersurfaces, alumina surfaces, and so on. Examples of functional groups ofmacrocyclic modules which can be used to couple to a substrate orsurface further include those described in the left hand column ofTables 2-4. Methods of initiating coupling of the modules to thesubstrate include chemical, thermal, photochemical, electrochemical, andirradiative methods.

[0258] Examples of spacer groups include polyethylene oxides,polypropylene oxides, polysaccharides, polylysines, polypeptides,poly(amino acids), polyvinylpyrrolidones, polyesters,polyvinylchlorides, polyvinylidene fluorides, polyvinylalcohols,polyurethanes, polyamides, polyimides, polysulfones, polyethersulfones,polysulfonamides, and polysulfoxides.

[0259] In one embodiment, the macrocyclic module composition comprises:from three to about twenty-four cyclic synthons coupled to form a closedring; at least two functional groups for coupling the closed ring tocomplementary functional groups on at least two other closed rings;wherein each functional group and each complementary functional groupcomprises a functional group containing atoms selected from the groupconsisting of C, H, N, O, Si, P, S, B, Al, halogens, and metals from thealkali and alkaline earth groups. The composition may comprise at leasttwo closed rings coupled through said functional groups. The compositionmay comprise at least three closed rings coupled through said functionalgroups.

[0260] In another embodiment, the macrocyclic module compositioncomprises: from three to about twenty-four cyclic synthons coupled toform a closed ring defining a pore; the closed ring having a first poredimension in a first conformation when a first group of substituents islocated at the pore and a second pore dimension in a second conformationwhen a second group of substituents is located at the pore; wherein eachsubstituent of each group comprises a functional group containing atomsselected from the group consisting of C, H, N, O, Si, P, S, B, Al,halogens, and metals from the alkali and alkaline earth groups.

[0261] In another embodiment, the macrocyclic module compositioncomprises: (a) from three to about twenty-four cyclic synthons coupledto form a closed ring defining a pore; (b) at least one functional groupcoupled to the closed ring at the pore and selected to transport aselected species through the pore, wherein the at least one functionalgroup comprises a functional group containing atoms selected from thegroup consisting of C, H, N, O, Si, P, S, B, Al, halogens, and metalsfrom the alkali and alkaline earth groups; (c) a selected species to betransported through the pore. The selected species may, in one example,be selected from the group of ovalbumin, glucose, creatinine, H₂PO₄ ⁻,HPO₄ ⁻², HCO₃ ⁻, urea, Na⁺, Li⁺, and K⁺.

[0262] In some embodiments, the cyclic synthons are each independentlyselected from the group consisting of benzene, cyclohexadiene,cyclohexene, cyclohexane, cyclopentadiene, cyclopentene, cyclopentane,cycloheptane, cycloheptene, cycloheptadiene, cycloheptatriene,cyclooctane, cyclooctene, cyclooctadiene, cyclooctatriene,cyclooctatetraene, naphthalene, anthracene, phenylene, phenanthracene,pyrene, triphenylene, phenanthrene, pyridine, pyrimidine, pyridazine,biphenyl, bipyridyl, decalin, piperidine, pyrrolidine, morpholine,piperazine, pyrazolidine, quinuclidine, tetrahydropyran, dioxane,tetrahydrothiophene, tetrahydrofuran, pyrrole, triptycene, adamantane,bicyclo[2.2.1]heptane, bicyclo[2.2.1]heptene, bicyclo[2.2.2]octane,bicyclo[2.2.2]octene, bicyclo[3.3.0]octane, bicyclo[3.3.0]octene,bicyclo[3.3.1]nonane, bicyclo[3.3.1]nonene, bicyclo[3.2.2]nonane,bicyclo[3.2.2]nonene, bicyclo[4.2.2]decane, 7-azabicyclo[2.2.1]heptane,1,3-diazabicyclo[2.2.1]heptane, and spiro[4.4]nonane.

[0263] In some embodiments, each coupled cyclic synthon is independentlycoupled to two adjacent synthons by a linkage selected from the groupconsisting of (a) a condensed linkage, and (b) a linkage selected fromthe group consisting of —NRC(O)—, —OC(O)—, —O—, —S—S—, —S—, —NR—,—(CRR′)_(p)—, —CH₂NH—, —C(O)S—, —C(O)O—, —C≡C—, —C≡C—C≡C—, —CH(OH)—,—HC═CH—, —NHC(O)NH—, —NHC(O)O—, —NHCH₂NH—, —NHCH₂CH(OH)CH₂NH—,—N═CH(CH₂)_(p)CH═N—, —CH₂CH(OH)CH₂—, —N═CH(CH₂)_(h)CH═N— where h is 1-4,—CH═N—NH—, —OC(O)O—, —OP(O)(OH)O—, —CH(OH)CH₂NH—, —CH(OH)CH₂—,—CH(OH)C(CH₃)₂C(O)O—,

[0264] wherein p is 1-6; wherein R and R′ are each independentlyselected from the group of hydrogen and alkyl; wherein the linkage isindependently configured in either of two possible configurations,forward and reverse, with respect to the synthons it couples together,if the two configurations are different structures; wherein Q is one ofthe synthons connected by the linkage.

[0265] In one variation, a macrocyclic module may be a closed ringcomposition of the formula:

[0266] wherein: the closed ring comprises a total of from three totwenty-four synthons Q; J is 2-23; Q¹ are synthons each independentlyselected from the group consisting of (a) aryl synthons, (b) heteroarylsynthons, (c) saturated cyclic hydrocarbon synthons, (d) unsaturatedcyclic hydrocarbon synthons, (e) saturated bicyclic hydrocarbonsynthons, (f) unsaturated bicyclic hydrocarbon synthons, (g) saturatedmulticyclic hydrocarbon synthons, and (h) unsaturated multicyclichydrocarbon synthons; wherein ring positions of each Q¹ which are notcoupled to a linkage L are independently substituted with hydrogen or afunctional group containing atoms selected from the group of C, H, N, O,Si, P, S, B, Al, halogens, and metals from the alkali and alkaline earthgroups; Q² is a synthon independently selected from the group consistingof (a) aryl synthons, (b) heteroaryl synthons, (c) saturated cyclichydrocarbon synthons, (d) unsaturated cyclic hydrocarbon synthons, (e)saturated bicyclic hydrocarbon synthons, (f) unsaturated bicyclichydrocarbon synthons, (g) saturated multicyclic hydrocarbon synthons,and (h) unsaturated multicyclic hydrocarbon synthons; wherein ringpositions of Q² which are not coupled to an L are independentlysubstituted with hydrogen or a functional group containing atomsselected from the group consisting of C, H, N, O, Si, P, S, B, Al,halogens, and metals from the alkali and alkaline earth groups; L arelinkages between the synthons each independently selected from the groupconsisting of synthon-synthon, —NRC(O)—, —OC(O)—, —O—, —S—S—, —S—, —NR—,—(CRR′)_(p)—, —CH₂NH—, —C(O)S—, —C(O)O—, —C≡C—, —C≡C—C≡C—, —CH(OH)—,—HC═CH—, —NHC(O)NH—, —NHC(O)O—, —NHCH₂NH—, —NHCH₂CH(OH)CH₂NH—,—N═CH(CH₂)_(p)CH═N—, —H₂CH(OH)CH₂—, —N═CH(CH₂)_(h)CH═N— where h is 1-4,—CH═N—NH—, —OC(O)O—, —OP(O)(OH)O—, —CH(OH)CH₂NH—, —CH(OH)CH₂—,—CH(OH)C(CH₃)₂C(O)O—,

[0267] wherein p is 1-6; wherein R and R′ are each independentlyselected from the group of hydrogen and alkyl; wherein the linkages Lare each independently configured with respect to the Q¹ and Q²synthons, each L having either of its two possible configurations withrespect to the synthons it couples together, the forward and reverseconfigurations of the linkage with respect to the immediately adjacentsynthons to which it couples, for example, Q¹ _(a)—NHC(O)—Q¹ _(b) and Q¹_(a)—C(O)NH—Q¹ _(b), if the two configurations are isomericallydifferent structures. Synthons Q¹, when independently selected, may beany cyclic synthon as described, so that the J synthons Q¹ may be foundin the closed ring in any order, for example,cyclohexyl--1,2-phenyl--piperidinyl--1,2-phenyl--1,2-phenyl--cyclohexyl,and so on, and the J linkages L may also be independently selected andconfigured in the closed ring. The macrocyclic modules represented andencompassed by the formula include all stereoisomers of the synthonsinvolved, so that a wide variety of stereoisomers of the macrocyclicmodule are included for each closed ring composition of synthons.

[0268] In other embodiments, the macrocyclic module may comprise aclosed ring composition of the formula:

[0269] wherein: J is 2-23; Q¹ are synthons each independently selectedfrom the group consisting of (a) phenyl synthons coupled to linkages Lat 1,2-phenyl positions, (b) phenyl synthons coupled to linkages L at1,3-phenyl positions, (c) aryl synthons other than phenyl synthons, (d)heteroaryl synthons other than pyridinium synthons, (e) saturated cyclichydrocarbon synthons, (f) unsaturated cyclic hydrocarbon synthons, (g)saturated bicyclic hydrocarbon synthons, (h) unsaturated bicyclichydrocarbon synthons, (i) saturated multicyclic hydrocarbon synthons,and (j) unsaturated multicyclic hydrocarbon synthons; wherein ringpositions of each Q¹ which are not coupled to a linkage L areindependently substituted with hydrogen or a functional group containingatoms selected from the group of C, H, N, O, Si, P, S, B, Al, halogens,and metals from the alkali and alkaline earth groups; Q² is a synthonindependently selected from the group consisting of (a) aryl synthonsother than phenyl synthons and naphthalene synthons coupled to linkagesL at 2,7-naphthyl positions, (b) heteroaryl synthons other than pyridinesynthons coupled to linkages L at 2,6-pyridino positions, (c) saturatedcyclic hydrocarbon synthons other than cyclohexane synthons coupled tolinkages L at 1,2-cyclohexyl positions, (d) unsaturated cyclichydrocarbon synthons other than pyrrole synthons coupled to linkages Lat 2,5-pyrrole positions, (e) saturated bicyclic hydrocarbon synthons,(f) unsaturated bicyclic hydrocarbon synthons, (g) saturated multicyclichydrocarbon synthons, and (h) unsaturated multicyclic hydrocarbonsynthons; wherein ring positions of Q² which are not coupled to an L areindependently substituted with hydrogen or a functional group containingatoms selected from the group consisting of C, H, N, O, Si, P, S, B, Al,halogens, and metals from the alkali and alkaline earth groups; L arelinkages between the synthons each independently selected from the groupconsisting of (a) a condensed linkage, and (b) a linkage selected fromthe group consisting of —NRC(O)—, —OC(O)—, —O—, —S—S—, —S—, —NR—,—(CRR′)_(p)—, —CH₂NH—, —C(O)S—, —C(O)O—, —C≡C—, —C≡C—C≡C—, —CH(OH)—,—HC═CH—, —NHC(O)NH—, —NHC(O)O—, —NHCH₂NH—, —NHCH₂CH(OH)CH₂NH—,—N═CH(CH₂)_(p)CH═N—, —CH₂CH(OH)CH₂—, —N═CH(CH₂)_(h)CH═N— where h is 1-4,—CH═N—NH—, —OC(O)O—, —OP(O)(OH)O—, —CH(OH)CH₂NH—, —CH(OH)CH₂—,—CH(OH)C(CH₃)₂C(O)O—,

[0270] wherein p is 1-6; wherein R and R′ are each independentlyselected from the group of hydrogen and alkyl; wherein linkages L areeach independently configured in either of two possible configurations,forward and reverse, with respect to the synthons it couples together,if the two configurations are different structures; wherein y is 1 or 2,and Q^(y) are each independently one of the Q¹ or Q² synthons connectedby the linkage.

[0271] In another embodiment, the macrocyclic module may comprise aclosed ring composition of the formula:

[0272] wherein: J is 2-23; Q¹ are synthons each independently selectedfrom the group consisting of (a) phenyl synthons coupled to linkages Lat 1,2-phenyl positions, (b) phenyl synthons coupled to linkages L at1,3-phenyl positions, and (c) cyclohexane synthons coupled to linkages Lat 1,2-cyclohexyl positions; wherein ring positions of each Q¹ which arenot coupled to a linkage L are independently substituted with hydrogenor a functional group containing atoms selected from the group of C, H,N, O, Si, P, S, B, Al, halogens, and metals from the alkali and alkalineearth groups; Q² is a cyclohexane synthon coupled to linkages L at1,2-cyclohexyl positions; wherein ring positions of Q² which are notcoupled to an L are independently substituted with hydrogen or afunctional group containing atoms selected from the group consisting ofC, H, N, O, Si, P, S, B, Al, halogens, and metals from the alkali andalkaline earth groups; L are linkages between the synthons eachindependently selected from the group consisting of (a) a condensedlinkage, and (b) a linkage selected from the group consisting of—NRC(O)—, —OC(O)—, —O—, —S—S—, —S—, —NR—, —(CRR′)_(p)—, —CH₂NH—,—C(O)S—, —C(O)O—, —C≡C—, —C≡C—C≡C—, —CH(OH)—, —HC═CH—, —NHC(O)NH—,—NHC(O)O—, —NHCH₂NH—, —NHCH₂CH(OH)CH₂NH—, —N═CH(CH₂)_(p)CH═N—,—CH₂CH(OH)CH₂—, —N═CH(CH₂)_(h)CH═N— where h is 1-4, —CH═N—NH—, —OC(O)O—,—OP(O)(OH)O—, —CH(OH)CH₂NH—, —CH(OH)CH₂—, —CH(OH)C(CH₃)₂C(O)O—,

[0273] wherein p is 1-6;

[0274] wherein R and R′ are each independently selected from the groupof hydrogen and alkyl; wherein linkages L are each independentlyconfigured in either of two possible configurations, forward andreverse, with respect to the synthons, it couples together, if the twoconfigurations are different structures; wherein y is 1 or 2, and Q^(y)are each independently one of the Q¹ or Q² synthons connected by thelinkage.

[0275] In another embodiment, the macrocyclic module comprises a closedring composition of the formula:

[0276] wherein: J is 2-23; Q¹ are synthons each independently selectedfrom the group consisting of (a) phenyl synthons coupled to linkages Lat 1,4-phenyl positions, (b) aryl synthons other than phenyl synthons,(c) heteroaryl synthons, (d) saturated cyclic hydrocarbon synthons, (e)unsaturated cyclic hydrocarbon synthons, (f) saturated bicyclichydrocarbon synthons, (g) unsaturated bicyclic hydrocarbon synthons, (h)saturated multicyclic hydrocarbon synthons, and (i) unsaturatedmulticyclic hydrocarbon synthons; wherein at least one of Q¹ is a phenylsynthon coupled to linkages L at 1,4-phenyl positions, and wherein ringpositions of each Q¹ which are not coupled to a linkage L areindependently substituted with hydrogen or a functional group containingatoms selected from the group of C, H, N, O, Si, P, S, B, Al, halogens,and metals from the alkali and alkaline earth groups; Q² is a synthonindependently selected from the group consisting of (a) aryl synthonsother than phenyl synthons and naphthalene synthons coupled to linkagesL at 2,7-naphthyl positions, (b) heteroaryl synthons, (c) saturatedcyclic hydrocarbon synthons other than cyclohexane synthons coupled tolinkages L at 1,2-cyclohexyl positions, (d) unsaturated cyclichydrocarbon synthons, (e) saturated bicyclic hydrocarbon synthons, (f)unsaturated bicyclic hydrocarbon synthons, (g) saturated multicyclichydrocarbon synthons, and (h) unsaturated multicyclic hydrocarbonsynthons; wherein ring positions of Q² which are not coupled to an L areindependently substituted with hydrogen or a functional group containingatoms selected from the group consisting of C, H, N, O, Si, P, S, B, Al,halogens, and metals from the alkali and alkaline earth groups; L arelinkages between the synthons each independently selected from the groupconsisting of (a) a condensed linkage, and (b) a linkage selected fromthe group consisting of —NRC(O)—, —OC(O)—, —O—, —S—S—, —S—, —NR—,—(CRR′)_(p)—, —CH₂NH—, —C(O)S—, —C(O)O—, —C≡C—, —C≡C—C≡C—, —CH(OH)—,—HC═CH—, —NHC(O)NH—, —NHC(O)O—, —NHCH₂NH—, —NCH₂CH(OH)CH₂NH—,—N═CH(CH₂)_(p)CH═N—, —CH₂CH(OH)CH₂—, —N═CH(CH₂)_(h)CH═N— where h is 1-4,—CH═N—NH—, —OC(O)O—, —OP(O)(OH)O—, —CH(OH)CH₂NH—, —CH(OH)CH₂—,—CH(OH)C(CH₃)₂C(O)O—,

[0277] wherein p is 1-6; wherein R and R′ are each independentlyselected from the group of hydrogen and alkyl; wherein linkages L areeach independently configured in either of two possible configurations,forward and reverse, with respect to the synthons it couples together,if the two configurations are different structures; wherein y is 1 or 2,and Q^(y) are each independently one of the Q¹ or Q² synthons connectedby the linkage.

[0278] In some embodiments, the functional groups are each independentlyselected from the group consisting of hydrogen, an activated acid, —OH,—C(O)OH, —C(O)H, —C(O)OCH₃, —C(O)Cl, —NRR, —NRRR⁺, —MgX, —Li, —OLi, —OK,—ONa, —SH, —C(O)(CH₂)₂C(O)OCH₃, —NH-alkyl-C(O)CH₂CH(NH₂)CO₂-alkyl,—CH═CH₂, —CH═CHR, —CH═CR₂, 4-vinylaryl, —C(O)CH═CH₂, —NHC(O)CH═CH₂,—C(O)CH═CH(C₆H₅),

[0279] —OH, —OC(O)(CH₂)₂C(O)OCH₃, —OC(O)CH═CH₂,

[0280] —P(O)(OH)(OX), —P(═O)(O⁻)O(CH₂)_(s)NR₃ ⁺; wherein R are eachindependently selected from the group consisting of hydrogen and 1-6Calkyl; X is selected from the group consisting of Cl, Br, and I; r is1-50; and s is 1-4.

[0281] In other embodiments, the macrocylic module may comprise a closedring composition of the formula:

[0282] wherein:

[0283] Q is

[0284]  J is from 1-22, and n is from 1-24; X and R^(n) are eachindependently selected from the group consisting of hydrogen or afunctional group containing atoms selected from the group consisting ofC, H, N, O, Si, P, S, B, Al, halogens, and metals from the alkali andalkaline earth groups; Z are each independently hydrogen or a lipophilicgroup; L are linkages between synthons each independently selected fromthe group consisting of (a) a condensed linkage, and (b) a linkageselected from the group consisting of —N═CR—, —NRC(O)—, —OC(O)—, —O—,—S—S—, —S—, —NR—, —(CRR′)_(p)—, —CH₂NH—, —C(O)S—, —C(O)O—, —C≡C—,—C≡C—C≡C—, —CH(OH)—, —HC═CH—, —NHC(O)NH—, —NHC(O)O—, —NHCH₂NH—,—NHCH₂CH(OH)CH₂NH—, —N═CHCH₂CH═N—, —N═CH(CH₂)_(h)CH═N— where h is 1-4,—CH═N—NH—, —OC(O)O—, —P(O)(OH)₂O—, —CH(OH)CH₂NH—, —CH(OH)CH₂—,—CH(OH)C(CH₃)₂C(O)O—,

[0285]  wherein p is 1-6; wherein R and R′ are each independentlyselected from the group of hydrogen and alkyl; wherein linkages L areeach independently configured in eitherof two possible configurations,forward and reverse, with respect to the synthons it couples together,if the two configurations are different structures.

[0286] In another embodiment, the macrocyclic module may comprise aclosed ring composition of the formula:

[0287] wherein:

[0288] Q is

[0289]  J is from 1-22, and n is from 1-48; X and R^(n) are eachindependently selected from the group consisting of functional groupscontaining atoms selected from the group consisting of C, H, N, O, Si,P, S, B, Al, halogens, and metals from the alkali and alkaline earthgroups; Z are each independently hydrogen or a lipophilic group; L arelinkages between the synthons each independently selected from the groupconsisting of (a) a condensed linkage, and (b) a linkage selected fromthe group consisting of —NRC(O)—, —OC(O)—, —O—, —S—S—, —S—, —NR—,—(CRR′)_(p)—, —CH₂NH—, —C(O)S—, —C(O)O—, —C≡C—, —C≡C—C≡C—, —CH(OH)—,—HC═CH—, —NHC(O)NH—, —NHC(O)O—, —NHCH₂NH—, —NHCH₂CH(OH)CH₂NH—,—N═CH(CH₂)_(p)CH═N—, —CH₂CH(OH)CH₂—, —N═CH(CH₂)_(n)CH═N— where h is 1-4,—CH═N—NH—, —OC(O)O—, —OP(O)(OH)O—, —CH(OH)CH₂NH—, —CH(OH)CH₂—,—CH(OH)C(CH₃)₂C(O)O—,

[0290]  wherein p is 1-6; wherein R and R′ are each independentlyselected from the group of hydrogen and alkyl; wherein linkages L areeach independently configured in either of two possible configurations,forward and reverse, with respect to the synthons it couples together,if the two configurations are different structures.

[0291] In some embodiments, X and R^(n) are each independently selectedfrom the group consisting of hydrogen, an activated acid, —OH, —C(O)OH,—C(O)H, —C(O)OCH₃, —C(O)Cl, —NRR, —NRRR⁺, —MgX, —Li, —OLi, —OK, —ONa,—SH, —C(O)(CH₂)₂C(O)OCH₃, —NH-alkyl-C(O)CH₂CH(NH₂)CO₂-alkyl, —CH═CH₂,—CH═CHR, —CH═CR₂, 4-vinylaryl, —C(O)CH═CH₂, —NHC(O)CH═CH₂,—C(O)CH═CH(C₆H₅),

[0292] —OH, —OC(O)(CH₂)₂C(O)OCH₃, —OC(O)CH═CH₂,

[0293] —P(O)(OH)(OX), —P(═O)(O⁻)O(CH₂)_(s)NR₃ ⁺;

[0294] wherein R are each independently selected from the groupconsisting of hydrogen and 1-6C alkyl; X is selected from the groupconsisting of Cl, Br, and I; r is 1-50; and s is 1-4.

[0295] In another embodiment, the macrocyclic module comprises theformula:

[0296] wherein:

[0297] Q is

[0298]  J is from 1-11, and n is from 1-12; X and R^(n) are eachindependently selected from the group consisting of hydrogen, anactivated acid, —OH, —C(O)OH, —C(O)H, —C(O)OCH₃, —C(O)Cl, —NRR, —NRRR⁺,—MgX, —Li, —OLi, —OK, —ONa, —SH, —C(O)(CH₂)₂C(O)OCH₃,—NH-alkyl-C(O)CH₂CH(NH₂)CO₂-alkyl, —CH═CH₂, —CH═CHR, —CH═CR₂,4-vinylaryl, —C(O)CH═CH₂, —NHC(O)CH═CH₂, —C(O)CH═CH(C₆H₅),

[0299]  —OH, —OC(O)(CH₂)₂C(O)OCH₃, —OC(O)CH═CH₂,

[0300]  —P(O)(OH)(OX), —P(═O)(O⁻)O(CH₂),NR₃ ⁺; wherein R are eachindependently selected from thegroup consisting of hydrogen and 1-6Calkyl; X is selected from the group consisting of Cl, Br, and 1; r is1-50; and s is 1-4; Z are each independently hydrogen or a lipophilicgroup; L are linkages between synthons each independently selected fromthe group consisting of (a) a condensed linkage, and (b) a linkageselected from the group consisting of —NRC(O)—, —OC(O)—, —O—, —S—S—,—S—, —NR—, —(CRR′)_(p)—, —CH₂NH—, —C(O)S—, —C(O)O—, —C≡C—, —C≡C—C≡C—,—CH(OH)—, —HC═CH—, —NHC(O)NH—, —NHC(O)O—, —NHCH₂NH—, —NHCH₂CH(OH)CH₂NH—,—N═CH(CH₂)_(p)CH═N—, —CH₂CH(OH)CH₂—, —N═CH(CH₂)_(h)CH═N— where h is 1-4,—CH═N—NH—, —OC(O)O—, —OP(O)(OH)O—, —CH(OH)CH₂NH—, —CH(OH)CH₂—,—CH(OH)C(CH₃)₂C(O)O—,

[0301]  wherein p is 1-6; wherein R and R′ are each independentlyselected from the group of hydrogen and alkyl; wherein linkages L areeach independently configured in either of two possible configurations,forward and reverse, with respect to the synthons it couples together,if the two configurations are different structures.

[0302] In another embodiment, the macrocyclic module has the formula:

[0303] wherein:

[0304] Q is

[0305]  J is from 1-11, and n is from 1-12; X and R^(n) are eachindependently selected from the group consisting of hydrogen, anactivated acid, —OH, —C(O)OH, —C(O)H, —C(O)OCH₃, —C(O)Cl, —NRR, —NRRR⁺,—MgX, —Li, —OLi, —OK, —ONa, —SH, —C(O)(CH₂)₂C(O)OCH₃,—NH-alkyl-C(O)CH₂CH(NH₂)CO₂-alkyl, —CH═CH₂, —CH═CHR, —CH═CR₂,4-vinylaryl, —C(O)CH═CH₂, —NHC(O)CH═CH₂, —C(O)CH═CH(C₆H₅),

[0306]  —OH, —OC(O)(CH₂)₂C(O)OCH₃, —OC(O)CH═CH₂,

[0307]  —P(O)(OH)(OX), —P(═O)(O⁻)O(CH₂)_(s)NR₃ ⁺; wherein R are eachindependently selected from the group consisting of hydrogen and 1-6Calkyl; X is selected from the group consisting of Cl, Br, and I; r is1-50; and s is 1-4; Z are each independently hydrogen or a lipophilicgroup; L are linkages between the synthons each independently selectedfrom the group consisting of (a) a condensed linkage, and (b) a linkageselected from the group consisting of —NRC(O)—, —OC(O)—, —O—, —S—S—,—S—, —NR—, —(CRR′)_(p)—, —CH₂NH—, —C(O)S—, —C(O)O—, —C≡C—, —C≡C—C≡C—,—CH(OH)—, —HC═CH—, —NHC(O)NH—, —NHC(O)O—, —NHCH₂NH—, —NHCH₂CH(OH)CH₂NH—,—N═CH(CH₂)_(p)CH═N—, —CH₂CH(OH)CH₂—, —N═CH(CH₂)_(h)CH═N— where h is 1-4,—CH═N—NH—, —OC(O)O—, —OP(O)(OH)O—, —CH(OH)CH₂NH—, —CH(OH)CH₂—,—CH(OH)C(CH₃)₂C(O)O—,

[0308]  wherein p is 1-6; wherein R and R′ are each independentlyselected from the group of hydrogen and alkyl; wherein linkages L areeach independently configured in either of two possible configurations,forward and reverse, with respect to the synthons it couples together,if the two configurations are different structures.

[0309] In another embodiment, the macrocyclic module comprises theformula:

[0310] wherein:

[0311] Q is

[0312]  J is from 1-11, and n is from 1-12; X is —NX¹— or —CX²X³, whereX¹ is selected from the group consisting of an amino acid residue,—CH₂C(O)CH₂CH(NH₂)CO₂-alkyl, and —C(O)CH═CH₂; X² and X³ are eachindependently selected from the group consisting of hydrogen, —OH, —NH₂,—SH, —(CH₂)_(t)OH, —(CH₂)_(t)NH₂ and —(CH₂)_(t)SH, wherein t is 1-4, andX² and X³ are not both hydrogen; R^(n) are each independently selectedfrom the group consisting of hydrogen, an activated acid, —OH, —C(O)OH,—C(O)H, —C(O)OCH₃, —C(O)Cl, —NRR, —NRRR⁺, —MgX, —Li, —OLi, —OK, —ONa,—SH, —C(O)(CH₂)₂C(O)OCH₃, —NH-alkyl-C(O)CH₂CH(NH₂)CO₂-alkyl, —CH═CH₂,—CH═CHR, —CH═CR₂, 4-vinylaryl, —C(O)CH═CH₂, —NHC(O)CH═CH₂,—C(O)CH═CH(C₆H₅),

[0313]  —OH, —OC(O)(CH₂)₂C(O)OCH₃, —OC(O)CH═CH₂,

[0314]  —P(O)(OH)(OX), —P(═O)(O⁻)O(CH₂)_(s)NR₃ ⁺; wherein R are eachindependently selected from the group consisting of hydrogen and 1-6Calkyl; X is selected from the group consisting of Cl, Br, and I; r is1-50; and s is 1-4; Z are each independently hydrogen or a lipophilicgroup; L are linkages between synthons each independently selected fromthe group consisting of (a) a condensed linkage, and (b) a linkageselected from the group consisting of —NRC(O)—, —OC(O)—, —O—, —S—S—,—S—, —NR—, —(CRR′)_(p)—, —CH₂NH—, —C(O)S—, —C(O)O—, —C≡C—, —C≡C—C≡C—,—CH(OH)—, —HC═CH—, —NHC(O)NH—, —NHC(O)O—, —NHCH₂NH—, —NHCH₂CH(OH)CH₂NH—,—N═CH(CH₂)_(p)CH═N—, —CH₂CH(OH)CH₂—, —N═CH(CH₂)_(h)CH═N— where h is 1-4,—CH═N—NH—, —OC(O)O—, —OP(O)(OH)O—, —CH(OH)CH₂NH—, —CH(OH)CH₂—,—CH(OH)C(CH₃)₂C(O)O—,

[0315]  wherein p is 1-6; wherein R and R′ are each independentlyselected from the group of hydrogen and alkyl; wherein linkages L areeach independently configured in either of two possible configurations,forward and reverse, with respect to the synthons it couples together,if the two configurations are different structures.

[0316] In another embodiment, the macrocyclic module has the formula:

[0317] wherein:

[0318] Q is

[0319]  J is from 1-11, and n is from 1-12; X and R^(n) are eachindependently selected from the group consisting of hydrogen, anactivated acid, —OH, —C(O)OH, —C(O)H, —C(O)OCH₃, —C(O)Cl, —NRR, —NRRR⁺,—MgX, —Li, —OLi, —OK, —ONa, —SH, —C(O)(CH₂)₂C(O)OCH₃,—NH-alkyl-C(O)CH₂CH(NH₂)CO₂-alkyl, —CH═CH₂, —CH═CHR, —CH═CR₂,4-vinylaryl, —C(O)CH═CH₂, —NHC(O)CH═CH₂, —C(O)CH═CH(C₆H₅),

[0320]  —OH, —OC(O)(CH₂)₂C(O)OCH₃, —OC(O)CH═CH₂,

[0321]  —P(O)(OH)(OX), —P(═O)(O⁻)O(CH₂)_(s)NR₃ ⁺; wherein R are eachindependently selected from the group consisting of hydrogen and 1-6Calkyl; X is selected from the group consisting of Cl, Br, and I; r is1-50; and s is 1-4; Z and Y are each independently hydrogen or alipophilic group; L are linkages between the synthons each independentlyselected from the group consisting of (a) a condensed linkage, and (b) alinkage selected from the group consisting of —NRC(O)—, —OC(O)—, —O—,—S—S—, —S—, —NR—, —(CRR′)_(p)—, —CH₂NH—, —C(O)S—, —C(O)O—, —C≡C—,—C≡C—C≡C—, —CH(OH)—, —HC═CH—, —NHC(O)NH—, —NHC(O)O—, —NHCH₂NH—,—NHCH₂CH(OH)CH₂NH—, —N═CH(CH₂)_(p)CH═N—, CH₂CH(OH)CH₂—,—N═CH(CH₂)_(h)CH═N— where h is 1-4, —CH═N—NH—, —OC(O)O—, —OP(O)(OH)O—,—CH(OH)CH₂NH—, —CH(OH)CH₂—, —CH(OH)C(CH₃)₂C(O)O—,

[0322]  wherein p is 1-6; wherein R and R′ are each independentlyselected from the group of hydrogen and alkyl; wherein linkages L areeach independently configured in either of two possible configurations,forward and reverse, with respect to the synthons it couples together,if the two configurations are different structures.

[0323] In another embodiment, the macrocyclic module has the fonnula:

[0324] wherein:

[0325] Q is

[0326]  J is from 1-11, and n is from 1-12; X and R^(n) are eachindependently selected from the group consisting of hydrogen, anactivated acid, —OH, —C(O)OH, —C(O)H, —C(O)OCH₃, —C(O)Cl, —NRR, —NRRR⁺,—MgX, —Li, —OLi, —OK, —ONa, —SH, —C(O)(CH₂)₂C(O)OCH₃,—NH-alkyl-C(O)CH₂CH(NH₂)CO₂-alkyl, —CH═CH₂, —CH═CHR, —CH═CR₂,4-vinylaryl, —C(O)CH═CH₂, —NHC(O)CH═CH₂, —C(O)CH═CH(C₆H₅),

[0327]  —OH, —OC(O)(CH₂)₂C(O)OCH₃, —OC(O)CH═CH₂,

[0328]  —P(O)(OH)(OX), —P(═O)(O⁻)O(CH₂)_(s)NR₃ ⁺; wherein R are eachindependently selected from the group consisting of hydrogen and 1-6Calkyl; X is selected from the group consisting of Cl, Br, and I; r is1-50; and s is 1-4; Z and Y are each independently hydrogen or alipophilic group; L are linkages between synthons each independentlyselected from the group consisting of (a) a condensed linkage, and (b) alinkage selected from the group consisting of —NRC(O)—, —OC(O)—, —O—,—S—S—, —S—, —NR—, —(CRR′)_(p)—, —CH₂NH—, —C(O)S—, —C(O)O—, —C≡C—,—C≡C—C≡C—, —CH(OH)—, —HC═CH—, —NHC(O)NH—, —NHC(O)O—, —NHCH₂NH—,—NHCH₂CH(OH)CH₂NH—, —N═CH(CH₂)_(p)CH═N—, —CH₂CH(OH)CH₂—,—N═CH(CH₂)_(h)CH═N— where h is 1-4, —CH═N—NH—, —OC(O)O—, —OP(O)(OH)O—,—CH(OH)CH₂NH—, —CH(OH)CH₂—, —CH(OH)C(CH₃)₂C(O)O—,

[0329]  wherein p is 1-6; wherein R and R′ are each independentlyselected from the group of hydrogen and alkyl; wherein linkages L areeach independently configured in either of two possible configurations,forward and reverse, with respect to the synthons it couples together,if the two configurations are different structures.

[0330] In some embodiments, the nanofilm may be coupled to a solidsupport selected from the group of Wang resins, hydrogels, aluminas,metals, ceramics, polymers, silica gels, sepharose, sephadex, agarose,inorganic solids, semiconductors, and silicon wafers.

[0331] In one embodiment, the nanofilm retains at least 85% of film areaafter thirty minutes on a Langmuir trough at 5-15 mN/m. In otherembodiments, the nanofilm retains at least 95% of film area after thirtyminutes on a Langmuir trough at 5-15 mN/m. In another embodiment, thenanofilm retains at least 98% of film area after thirty minutes on aLangmuir trough at 5-15 mN/m.

[0332] In one embodiment, a method for making a macrocyclic modulecomposition comprises: (a) providing a plurality of a first cyclicsynthon; (b) contacting a plurality of a second cyclic synthon with thefirst cyclic synthons; (c) isolating the macrocyclic module composition.The method may further comprise contacting a linker molecule with themixture in (a) or (b).

[0333] In another embodiment, a method for making a macrocyclic modulecomposition comprises: (a) providing a plurality of a first cyclicsynthon; (b) contacting a plurality of a second cyclic synthon with thefirst cyclic synthons; (c) contacting a plurality of the first cyclicsynthon with the mixture from (b).

[0334] In another embodiment, a method for making a macrocyclic modulecomposition comprises: (a) providing a plurality of a first cyclicsynthon; (b) contacting a plurality of a second cyclic synthon with thefirst cyclic synthons; (c) contacting a plurality of a third cyclicsynthon with the mixture from (b).

[0335] The method may further comprise contacting a linker molecule withthe mixture in (a) or (b) or (c). The method may further comprisesupporting a cyclic synthon or coupled synthons on a solid phase.

[0336] In another embodiment, a method for making a macrocyclic modulecomposition comprises: (a) contacting a plurality of cyclic synthonswith a metal complex template; and (b) isolating the macrocyclic modulecomposition.

[0337] In another embodiment, a method of preparing a composition fortransporting a selected species through the composition comprises:selecting a first cyclic synthon, wherein the first cyclic synthon issubstituted with at least one functional group comprising a functionalgroup containing atoms selected from the group consisting of C, H, N, O,Si, P, S, B, Al, halogens, and metals from the alkali and alkaline earthgroups; selecting from two to about twenty-three additional cyclicsynthons; incorporating the first cyclic synthon and the additionalcyclic synthons into a macrocyclic module composition comprising: fromthree to about twenty-four cyclic synthons coupled to form a closed ringdefining a pore; wherein the at least one functional group of the firstcyclic synthonhis located at the pore of the macrocyclic modulecomposition and is selected to transport the selected species throughthe pore.

[0338] Macrocyclic Module Pores

[0339] An individual macrocyclic module may include a pore in itsstructure. The size of the pore may determine the size of molecules orother species which can pass through the macrocyclic module. The size ofa pore in a macrocyclic module may depend on the structure of thesynthons used to make the macrocyclic module, the linkages betweensynthons, the number of synthons in a module, the structure of anylinker molecules used to make the macrocyclic module, and otherstructural features of the macrocyclic module whether inherent in thepreparation of the macrocyclic module or added in later steps ormodifications. Stereoisomerism of macrocyclic modules may also be usedto regulate the size of a pore of a macrocyclic module by variation ofthe stereoisomer of each synthon used to prepare the closed ring of themacrocyclic module.

[0340] The dimension of a pore in a macrocyclic module may be varied bychanging the combination of synthons used to form the macrocyclicmodule, or by varying the number of synthons in the closed ring. Thedimension of a pore may also be varied by substituents on the synthonsor linkages. The pore may therefore be made large enough or small enoughto achieve an effect on transport of species through the pore. Specieswhich may be transported through the pore of a macrocyclic moduleinclude atoms, molecules, biomolecules, ions, charged particles, andphotons.

[0341] The size of a species may not be the sole determinant of whetherit will be able to pass through a pore of a macrocyclic module. Groupsor moieties located in or near the pore structure of a macrocyclicmodule may regulate or affect transport of a species through the pore byvarious mechanisms. For example, transport of a species through the poremay be affected by groups of the macrocyclic module which interact withthe species, by ionic or other interaction, such as chelating groups, orby complexing the species. For example, a charged group such as acarboxylate anion or ammonium group may couple an oppositely-chargedspecies and affect its transport. Substituents of synthons in amacrocyclic module may affect the passage of a species through the poreof the macrocyclic module. Groups of atoms which render the pore of amacrocyclic module more or less hydrophilic or lipophilic may affecttransport of a species through the pore. An atom or group of atoms maybe located within or proximate to a pore to sterically slow or block thepassage of a species through the pore. For example, hydroxyl or alkoxygroups may be coupled to a cyclic synthon and located in the pore of thestructure of the macrocyclic module, or may be coupled to a linkagebetween synthons and located in the pore. A wide range of functionalgroups may be used to sterically slow or block the passage of a speciesthrough the pore, including functional groups containing atoms selectedfrom the group consisting of C, H, N, O, Si, P, S, B, Al, halogens, andmetals from the alkali and alkaline earth groups. Blocking and slowingpassage of a species through the pore may involve reducing the dimensionof the pore by steric blocking, as well as slowing the passage ofspecies by creating a path through the pore which is not linear, andproviding interaction between the functional group and the species toslow transport. The stereochemical structure of the portion of themacrocyclic module which defines the pore and its interior may alsoaffect transport. Any groups or moieties which affect transport of aspecies through the pore of a macrocyclic module may be introduced aspart of the synthons used to prepare the macrocyclic module, or may beadded later by various means. For example, S7-1 could be reacted withClC(O)(CH₂)₂C(O)OCH₂CH₃ to convert the phenol groups to succinyl estergroups. Further, molecular dynamical motion of the synthons and linkagesof a partly flexible macrocyclic module may affect transport of aspecies through the pore of the module. Transport behavior may not bedescribed solely by the structure of the macrocyclic module itself sincethe presence of the species which is to be transported through the poreaffects the flexibility, conformation, and dynamical motions of amacrocyclic module. In general, solvent may also affect transport ofsolutes through a pore.

[0342] The following examples further describe and demonstratevariations within the scope of the present invention. All examplesdescribed in this specification, both in the description above and theexamples below, are given solely for the purpose of illustration and arenot to be construed as limiting the present invention. While there havebeen described illustrative variations of this invention, those skilledin the art will recognize that they may be changed or modified withoutdeparting from the spirit and scope of this invention, and it isintended to cover all such changes, modifications, and equivalentarrangements that fall within the true scope of the invention as setforth in the appended claims.

[0343] All documents referenced herein, including applications forpatent, patent references, publications, articles, books, and treatises,are specifically incorporated by reference herein in their entirety.

EXAMPLES

[0344] Reagents were obtained from Aldrich Chemical Company and VWRScientific Products. The Langmuir trough used was a KSV minitrough (KSVInstruments, Trumbull, Conn.). Interfacial rheometry was performed usinga CIR-100 Interfacial Rheometer (Rheometric Scientific, Piscataway N.J.)with a KSV Langmuir two-barrier rheology microtrough having a width of85 mm (KSV Instruments, Trumbull, Conn.). Rates of surface compressionare reported as the linear rate of barrier movement. Atomic forcemicroscopy (AFM) images were obtained with a PicoSPM (Molecular Imaging,Pheonix Ariz.). Contact Mode images were typically recorded underflowing nitrogen with an Si point probe tip.

Example 1

[0345] Derivatization of SiO₂ Substrates with(3-aminopropyl)triethoxysilane (APTES): SiO₂ substrates were firstsonicated in a piranha solution (3:1 ratio of H₂SO₄:30% H₂O₂) for 15minutes. This was followed by a 15 min sonication in Milli-Q water (>18MΩ-cm). The derivatization step was done in a glove bag under a N₂atmosphere. 0.05 mL APTES and 0.05 mL pyridine were added to 9 mL oftoluene. Immediately following mixing, the freshly cleaned SiO₂substrates were immersed in the APTES solution for 10 min. Substrateswere washed with copious amounts of toluene and then dried with N₂.Deposited APTES films showed a range of thickness values from 0.8 to 1.3nm.

Example 2

[0346] Deposition of Hexamer 1dh/PMAOD nanofilm on APTES modified SiO₂substrate: A 50%:50% area fraction solution of Hexamer 1dh:poly(maleicanhydride-alt-1-octadecene) (PMAOD) (Aldrich, 30,000-50,000 MW) wasspread onto a pH 9 water subphase. After 10 minutes the film wascompressed to 12 mN/m at a rate of 3 mm/min. Upon compression a layer ofnanofilm was deposited onto an APTES-modified substrate on the upstrokeusing a vertical dip. The deposition rate was typically 0.25 or 0.5mm/min. Following deposition, the nanofilm was heated at 70° C. under N₂for about 6 hours.

[0347] Imaging ellipsometry, illustrated in FIG. 1A, revealed an APTEScoating on the substrate having a thickness of 0.94 nm. The thickness ofthe coating and deposited nanofilm, illustrated on the left in FIG. 1B,was 1.94 nm, while the thickness of the APTES coating of the substrate,illustrated on the right in FIG. 1B, was 0.82 nm. Thus, the thickness ofthe uncured nanofilm itself was 1.1 nm. A smooth, physicallyhomogeneous, continuous and unbroken nanofilm was deposited. Afterheating, the thickness of the coating and cured nanofilm was 1.57 nm,illustrated on the left in FIG. 1C, while the APTES coating of thesubstrate, illustrated on the right in FIG. 1C, was 0.53 nm. Thus, thethickness of the nanofilm itself was virtually unchanged at 1.0 nm.After sonication in CHCl₃ (FIG. 2A), acetone (FIG. 2B), and water (FIG.2C), each for five minutes, the thickness of the nanofilm itself wasvirtually unchanged at 0.9 nm, 1.0 nm, and 1.0 nm, respectively. Thus,ellipsometric measurements determined that the loss of nanofilm materialfrom the substrate upon sonication was minimal.

Example 3

[0348] Deposition of Hexamer 1dh/PMAOD/DEM nanofilm on APTES modifiedSiO₂ substrate: A 0.1:0.9 mole fraction solution of Hexamer 1dh:PMAODwas spread onto a pH 9 diethyl malonimidate (DEM) subphase (0.5 mg/mL inaqueous solution). After 10 minutes the film was compressed to 12 mN/mat a rate of 2 mm/min. Upon compression a layer of nanofilm wasdeposited onto the APTES modified substrate on the upstroke using avertical dip. The deposition rate was typically 0.5 or 1.0 mm/min.Following deposition, the nanofilm was cured at 80° C. under N₂ for14-19 hours to attach the nanofilm to the surface. A nanofilm thicknessof 1.1 nm was measured by ellipsometry before curing the nanofilm, and0.9-1.0 nm after curing. A smooth, physically homogeneous, continuousand unbroken nanofilm was deposited. After sonication in CHCl₃ at roomtemperature a nanofilm thickness of 0.7-0.9 nm was measured byellipsometry.

Example 4

[0349] Deposition of Hexamer 1dh/PMAOD/DEM nanofilm on APTES modifiedSiO₂ substrate: A nanofilm of Hexamer 1dh and PMAOD was prepared as inExample 3, except at deposition surface pressure of 25 mN/m. A smooth,physically homogeneous, continuous and unbroken nanofilm was depositedfor DEM subphase concentrations of 0.5 mg/mL and 2.0 mg/mL. Aftersonication in CHCl₃ at room temperature a thickness of 1.2 nm wasmeasured by ellipsometry for nanofilm on bare SiO₂ substrate, and athickness of 1.4-1.6 nm was measured by ellipsometry for nanofilm onAPTES modified SiO₂ substrate.

Example 5

[0350] Surface rheology of a sample of nanofilm of Hexamer 1dh and DEMhaving polymeric component PMAOD is shown in Table 10. Referring toTable 10, as the area fraction of Hexamer 1dh decreased, correspondingto an increase in polymeric component PMAOD, the surface moduli of thenanofilm substantially decreased. G′ indicates storage modulus and G″indicates loss modulus. TABLE 10 Rheology of nanoflim of Hexamer 1dh andDEM having polymeric component PMAOD SURFACE MODULI AREA FRACTION OFHEXAMER (φ) G′, G″ 0.0 0.6 0.8 0.9 0.95 1.0 G′ @ 10 mN/m 0.2 5.9 15.15.0 6.1 13.3 G″ @ 10 mN/m 7.5 88.2 163.1 97.3 151.4 257.4 G′ @ 20 mN/m6.6 45.3 65.8 58.8 57.5 147.4 G″ @ 20 mN/m 154.7 412.8 474.6 501.7 570.71269.9 G′ @ 30 mN/m 35.05 — — — 153.5 418.5 G″ @ 30 mN/m 391.1 — — —859.6 2707.2

[0351] As shown in Table 10, G″ typically exceeds G′ in the viscousnanofilm. The data in Table 10 indicate that for a nanofilm of Hexamer1dh and DEM, introducing an area fraction of polymeric component PMAODof about 5% into the nanofilm reduced the moduli of thle nanofilm bymore than 50%. The polymeric component makes the nanofilm more flexibleand less brittle. In other words, the data in Table 10 indicate that fora nanofilm having an area fraction of polymeric component PMAOD of about5%, the surface loss modulus of the nanofilm at a surface pressure from5-30 mN/m is less than about 50% of the surface loss modulus of the samenanofilm composition made without the polymeric components.

[0352] To prepare the nanofilms used in Table 10, chloroform solutionsof Hexamer 1dh and PMAOD were mixed in proportions corresponding toTable 10, and allowed to equilibrate at room temperature forapproximately one hour. Subsequently, 10 μl of the chloroform mixturewere spread at the liquid-air interface of a 50 mM NaHCO₃ buffer (pH 9)containing 0.5 mg/ml DEM. After allowing 15 minutes for evaporation ofthe spreading solvent, the nanofilm was compressed to a surface pressureof 10 mN/m. The viscoelastic properties of the nanofilm were thenmeasured using a CIR-100 interfacial rheometer (Camtel Ltd, Herts, UK).A sinusoidal torque of amplitude 0.02 μN*m and frequency 1 Hz wasapplied to the nanofilm, and the in-phase and out-of-phase components ofthe resulting strain were measured, giving the elastic and viscouscomponents, respectively. For the data in Table 10, the response wasaveraged over about 40 minutes.

[0353] Surface rheology of a sample of nanofilm of Hexamer 1dh and DEMhaving polymeric component PMAOD is shown in FIG. 3A. Nanofilms used inFIG. 3A were prepared with a 2.0 mg/ml DEM subphase. The dashed linecurves in FIG. 3A were obtained with a subphase heated to 33° C., whilethe solid line curves were obtained with a subphase at room temperature22° C. The data in FIG. 3A indicate that for a nanofilm of Hexamer 1dhand DEM, introducing an area fraction of PMAOD of about 20% into thenanofilm reduced the loss modulus (G″) of the nanofilm by about one-halfat 10 mN/m surface pressure. The data in FIG. 3A also indicate that themodulus of the nanofilm is generally higher for the higher subphasetemperature.

[0354] Surface rheology of a sample of nanofilm of Hexamer 1dh and DEMhaving polymeric component PMAOD is shown in FIGS. 3B-D. Nanofilms usedin FIGS. 3B-D were prepared with a 2.0 mg/ml DEM subphase at roomtemperature. The data in FIGS. 3B-D indicate that for a nanofilm ofHexamer 1dh and DEM, introducing an area fraction of polymeric componentPMAOD of about 5% into the nanofilm reduced the storage and loss moduliof the nanofilm by more than one-half at 20 mN/m surface pressure orgreater.

Example 6

[0355] Hexamer 1dh, PMAOD and DEM on polycarbonate track etch membrane(PCTE): A nanofilm of Hexamer 1dh, PMAOD, and DEM can be made to spanthe pores of a 0.01 μm PCTE. A solution of Hexamer 1dh and PMAOD having0.1 mole fraction hexamer: 0.9 mole fraction PMAOD was spread onto asubphase of 0.5 mg/ml DEM. One layer of the resulting nanofilm wasdeposited by vertical dip at 2 mm/min at a surface pressure of 12 mN/mand deposition rate 1 mm/min onto a PCTE having holes of 10 nm diameter.The sample was not heated. The PCTE substrates were not plasma treated,and the attachment of the nanofilm to the PCTE was not necessarily bycovalent binding, but may have been by weaker types of binding orcoupling.

[0356] The scanning electron micrographs of this nanofilm are shown inFIG. 4. FIG. 4A shows an area in the center of the nanofilm in which noholes in the nanofilm were visible. FIG. 4B shows an area far from theedge of the nanofilm in which no holes in the nanofilm were visible.FIG. 4C shows an area next to that in FIG. 4D which was near the edge ofthe nanofilm and in which a few holes of various sizes may have beenvisible in the nanofilm. In FIG. 4D is shown an area near the edge ofthe nanofilm in which a few holes of various sizes may have been visiblein the nanofilm. The holes observed in the nanofilm in FIGS. 4A-4D mayhave been as large as 30 nm in diameter.

[0357] By comparison, the scanning electron micrograph of a PCTEsubstrate having holes of 10 nm diameter is shown in FIG. 5A, whichillustrates the pattern of holes in the substrate. The scanning electronmicrograph of the same PCTE substrate after plasma treatment is shown inFIG. 5B, which illustrates that the holes may be widened as compared tothe PCTE substrate used in FIG. 5A.

Example 7

[0358] The FTIR-ATR spectrum of CHCl₃ rinsings from PMAOD Langmuir thinfilm deposited on a SiO₂ substrate from an aqueous subphase is shown inFIG. 6. The absorbance at 1737 cm⁻¹ (acid carbonyl) resulted from thehydrolysis of the anhydride group to form a diacid.

Example 8

[0359] The FTIR-ATR spectrum of Hexamer 1dh is shown in FIG. 7. Thedominant absorbance at 1450 cm⁻¹ was from the —CH₂— stretching of thealkyl chains of the hexamer.

Example 9

[0360] The FTIR-ATR spectrum of CHCl₃ rinsings from a nanofilm ofHexamer 1dh and PMAOD deposited on a SiO₂ substrate from a pH 9 aqueoussubphase is shown in FIG. 8. The peak at 1737 cm⁻¹ revealed that thediacid form was present. The broadening of this peak and the formationof a shoulder at 1713 cm⁻showed that ester and amide bond formationoccurred. Ester formation (shoulder at 1713 cm⁻¹) appeared to be favoredover an amide carbonyl absorbance (1630-1680 cm⁻¹). In the PMAODspectrum (FIG. 6), the ratio of the areas of the peak appearing at 1450cm⁻¹ to the peak at 1737 cm⁻¹ was about 3:1. The ratio for the samepeaks observed in FIG. 8 was less than one, and indicated ester or amideformation because of the increase in absorbance in the carbonyl region.This indicated coupling of the module via the phenol and secondary aminegroups to the PMAOD polymer.

Example 10

[0361] The FTIR-ATR spectrum of CHCl₃ rinsings from a Hexamer 1dhLangmuir film deposited on a SiO₂ substrate from a pH 9 DEM subphase isshown in FIG. 9. Absorbances at 1737 cm⁻¹ and 1713 cm⁻¹ were observed.The carbonyl absorbance showed that amide linkages may have formed,indicating coupling of between the module and the cross-linker.

Example 11

[0362] The FTIR-ATR spectrum of CHCl₃ rinsings from a nanofilm made fromHexamer 1dh and PMAOD deposited on a SiO₂ substrate from a pH 9 DEMsubphase is shown in FIG. 10. The carbonyl region resembles that in FIG.8, which would be expected as the DEM can react with the aminefunctionality of the hexamer to form amide cross-links. In addition,ester formation is possible between PMAOD and the hexamer. Thisindicated coupling between the module and the polymer, and between themodule and the cross-linker.

Example 12

[0363] Contact Mode AFM images of plasma treated PCTE are shown in FIG.11. The surface of this substrate was partially smoothed using the AFMtip, as shown in the bottom panel of FIG. 11.

Example 13

[0364] A nanofilm of 0.8:0.2 mole fraction Hexamer 1dh:PMAOD which werepre-mixed in solution was prepared, and deposited by vertical dip ontoAPTES coated SiO₂ substrate. The nanofilm was cured at 70° C. under N₂for 15 hours. The Contact Mode AFM images of the nanofilm obtained underflowing N₂ are shown in FIG. 12A. Referring to FIG. 12A, the top panelsshow the images of a continuous nanofilm, while the bottom panels showthe images of the same nanofilm after a piece of the nanofilm about 250nm² in area was removed by scraping with the AFM tip. The thickness ofthe film observed at the edge of the hole created by the tip was 2-3 mm.A second nanofilm of the same composition was cured at 70° C. under N₂for 39 hours. The Contact Mode AFM images of the second nanofilmobtained under flowing N₂ are shown in FIG. 12B. Referring to FIG. 12B,the top panels show the images of a continuous nanofilm, while thebottom panels show the images of the same nanofilm after an attempt toscrape away a piece of the nanofilm with the AFM tip. The nanofilm couldnot be scraped away, showing that the longer-cured nanofilm was morestrongly attached to the substrate by annealing.

Example 14

[0365] The Contact Mode AFM image of a nanofilm made from Hexamer 1dhand PMAOD and DEM, having 0.10 mole fraction of Hexamer 1dh:0.90 molefraction PMAOD is shown in FIG. 13. The nanofilm was deposited byvertical dip onto PCTE having a random array of holes 0.01 μm indiameter. A depression in the nanofilm made with the AFM tip is clearlyvisible.

Example 15

[0366] A nanofilm was made from an amphiphile, octadecylamine (ODA), andan amphiphilic polymer, polymethylmethacrylate (PMMA) (Polysciences,Warrington Pa., MW 100,000, polydispersity 1.1), from a chloroformsolution of the two components heated to 55° C. for 18 hours, thenspread at the liquid-air interface of a 100 mM NaH₂PO₄ buffer (pH 7.3)at room temperature. Isotherms of this nanofilm and its components madewith a 1:1 mixture of ODA:PMMA, illustrated in FIG. 14, showed that theisotherms of ODA and PMMA each retained substantially the same shape inthe nanofilm. In general, the isotherms of FIG. 14 indicate that ODA andPMMA were immiscible in the nanofilm.

Example 16

[0367] A nanofilm was made from an amphiphile, ODA, and an amphiphilicpolymer, PMAOD, by spreading a 1:1 molar ratio of ODA:PMAOD inchloroform at the liquid-air interface. The isotherm of this nanofilm,illustrated in FIG. 15, exhibited a different shape than either of thecomponents alone, and a much higher mean molecular area than either ofthe components alone. In general, the isotherm of FIG. 15 indicates thatODA and PMAOD were miscible in the nanofilm.

Example 17

[0368] A solution of Hexamer 1dh and PMMA was spread at the liquid-airinterface over a water subphase to form a nanofilm having 0.6 areafraction Hexamer 1dh. One layer of the resulting nanofilm was depositedby vertical dip at a surface pressure of 20 mN/m onto an APTES coatedsilicon substrate. The Contact Mode AFM image of the deposited nanofilmis shown in FIG. 16 and illustrates a phase separated nanofilmcomposition, which confirms that the Hexamer 1dh/PMMA mixture isimmiscible. The height of the continuous phase was about 1 nm above thediscontinuous phase. Deformations were made with the AFM probe tip ineach of the continuous phase and the discontinuous phase to confirm thatthe two phases are composed of nanofilm and were not part of thesubstrate. By comparison, the ellipsometric image of a Langmuir-Blodgettdeposition of PMMA alone showed a homogeneous, continuous and unbrokenfilm of about 0.6-1.0 nm thickness.

Example 18

[0369] A solution of Hexamer 1dh and PMAOD was spread at the liquid-airinterface over a water subphase containing 2 mg/ml DEM to form ananofilm. Surface rheology of this nanofilm is shown in FIG. 17.Referring to FIG. 17, storage and loss surface moduli of the nanofilmare illustrated over time as the temperature of the subphase was raised.T_(bath) indicates the temperature of the surrounding circulation bath,and T° C. indicates the temperature of the subphase.

Example 19

[0370] A solution of Hexamer 1dh and poly(2-hydroxyethyl methacrylate)(PHEMA) was spread at the liquid-air interface over a water subphasecontaining 2 mg/ml DEM to form a nanofilm.

[0371] Surface rheology of this nanofilm is shown in Table 11. Referringto Table 11, storage and loss surface moduli of the nanofilm areillustrated as the mole fraction of the components was varied. TABLE 11Rheology of nanofilm of Hexamer 1dh and DEM having polymeric componentPHEMA mol fraction 10 mN/m 20 mN/m 30 mN/m Hexamer 1dh G′ G″ G′ G″ G′ G″0 0.07*  14* — — — — 0.5 32 649 138 1233 291 1660 0.75 5.8 172  64  660172 1206 100 13.3 257 147 1297 419 2707

[0372] The data in Table 11 indicate that for a nanofilm of Hexamer 1dh,PHEMA and DEM, introducing a mole fraction of polymeric component PHEMAof about 25% into the nanofilm reduced the loss modulus (G″) of thenanofilm by more than 50% at 30 mN/m surface pressure. In Table 11, theincrease of both loss and storage surface moduli of the nanofilm as themole fraction of PHEMA increases from 0.25 to 0.5 indicates coupling ofPHEMA to the cross-linker.

Example 20

[0373] Rheological characterization of polyglycidyl methacrylate (PGM)monolayers on a subphase containing 1% (by volume) ethylene diamine wasperformed according to the following protocol. 10 μl of a chloroformsolution of PGM (1 mg/mL) was spread at the liquid-air interface of a 1%ethylene diamine subphase. After allowing 15 minutes for evaporation ofthe spreading solvent, the film was compressed to a surface pressure of10 mN/m. The viscoelastic properties of the film were then measured at30° C. using the CIR-100 interfacial rheometer (Camtel LTD, Herts, UK).Briefly, a sinusoidal torque of amplitude 0.02 μN·m and frequency 1 Hzwas applied to the film, and the in-phase and out-of-phase components ofthe resulting strain were measured, giving the elastic and viscouscomponents, respectively. The response was measured for approximately 70minutes, and the data were then averaged. Subsequently, a controlexperiment was performed with PGM on basic subphases (pH=10.5 and 12) todetermine whether pH played any roll in the high viscosities observedfor experiments performed on the ethylene diamine subphases. TheRheology data in FIG. 18 indicates that the PGM films made on anethylene diamine subphase have an almost 2 orders of magnitude increasein surface moduli, as compared to PGM on a basic subphase. Therefore,ethylene diamine appears to be cross-linking the PGM into a nanofilm.When spread on a pure H₂O subphase, PGM makes a Langmuir film with acollapse pressure of approximately 10 mN/m (data not shown).

Example 21

[0374] Without intending to be bound by any one particular theory, onemethod to approximate pore size of a macrocyclic module is quantummechanical (QM) and molecular mechanical (MM) computations. In thisexample, macrocyclic modules having two types of synthons, “A” and “B,”were used and all linkages between synthons were assumed to be the same.For the purposes of QM and MM computations, the root mean squaredeviations in the pore areas were computed over dynamic runs.

[0375] For QM, each module was first optimized using the MM+ force fieldapproach of Allinger (JACS, 1977, 99:8127) and Burkert, et al.,(Molecular Mechanics, ACS Monograph 177, 1982). They were thenre-optimized using the AM1 Hamiltonian (Dewar, et al., JACS, 1985,107:3903; Dewar, et al., JACS, 1986, 108:8075; Stewart, J. Comp. AidedMol. Design, 1990, 4:1). To verify the nature of the potential energysurface in the vicinity of the optimized structures, the associatedHessian matrices were computed using numerical double-differencing.

[0376] For MM, the OPLS-AA force field approach (Jorgensen, et al.,JACS, 1996, 118:11225) was used. For imine linkages, the dihedral anglewas confined to 180°±10°. The structures were minimized and equilibratedfor one picosecond using 0.5 femtosecond time steps. Then a 5 nanoseconddynamics run was carried out with a 1.5 femtosecond time step.Structures were saved every picosecond. The results are shown in Tables12 and 13.

[0377] Macrocyclic module pore areas derived from QM and MM computationsfor various linkages and macrocyclic module pore size are shown in Table12. In Table 12, the macrocyclic modules had alternating synthons “A”and “B.” Synthon “A” is a benzene synthon coupled to linkages L at1,3-phenyl positions, and Synthon “B” is shown in the left-hand columnof the table. TABLE 12 Pore areas for various macrocyclic modules (Å²)TETRAMER TETRAMER HEXAMER HEXAMER OCTAMER OCTAMER SYNTHON B QM MM QM MMQM MM trans-1,2- imine (trans) Imine (trans) cyclohexane 14.3 Å² 13.2 ±1.4 Å² trans-1,2- Acetylene cyclohexane 14.3 Å² trans-1,2- Amine Aminecyclohexane 23.1 Å² 13.9 ± 1.9 Å² trans-1,2- Amide Amide cyclohexane19.7 Å² 17.5 ± 2.0 Å² trans-1,2- Ester Ester cyclohexane 18.9 Å² 19.6 ±2.0 Å² Equatorial-1,3- imine (trans) Imine (trans) imine (trans) Imine(trans) cyclohexane 18.1 Å² 21.8 ± 1.6 Å² 66.2 Å² 74.5 ± 7.7 Å² Equatorial-1,3- Amine Amine cyclohexane 14.7 Å² 19.9 ± 2.6 Å²Equatorial-1,3- Amide Amide cyclohexane 24.8 Å² 21.7 ± 1.8 Å²Equatorial-1,3- Ester Ester cyclohexane 22.9 Å² 22.8 ± 2.4 Å²Equatorial-3- imine (trans) imine (trans) imine (trans) Imine (trans)imine (trans) Imine (trans) amino- oxygen- oxygen-oxygen 18.4 Å² 21.0 ±1.5 Å² 56.7 Å² 60.5⁺ − 8.3 Å²    cyclohexene oxygen  distance distance3.7 ± .3 Å 2.481 Å trans-1,2- imine (trans) Imine (trans) pyrrolidine10.4 Å²  9.2 ± 1.4 Å² Equatorial-1,3- imine (trans) Imine (trans)piperidene 19.2 Å² 20.9 ± 1.1 Å² Endo-exo-1,2- imine (trans) Imine(trans) bicycloheptane 11.1 Å² 14.1 ± + − 11 Å²   Endo-endo-1,3- imine(trans) Imine (trans) bicycloheptane 18.8 Å² 20.7 ± 1.4 Å² Endo-exo-1,3-Imine Imine bicycloheptane 19.5 Å² 10.1 ± + 4.9 Å²   Equatorial-1,3-Amine Amine cyclohexane  9.8 Å²  9.9 ± 2.4 Å² Endo-endo-1,3- imine(trans) Imine (trans) bicyclooctene 18.9 Å² 21.6 ± 1.5 Å² Endo-exo-1,3-imine (trans) Imine (trans) bicyclooctene 15.6 Å² 18.7 ± 1.6 Å²Equatorial-3,9- imine (trans) Imine (trans) decalin 35.4 Å² 40.0 ± 2.2Å²

[0378] Further macrocyclic module pore areas derived from QM and MMcomputations for various linkages and macrocyclic module pore size areshown in Table 13. In Table 13, the macrocyclic modules had alternatingsynthons “A” and “B.” In Table 13, Synthon “A” is a naphthalene synthoncoupled to linkages L at 2,7-naphthyl positions, and Synthon “B” isshown in the left-hand column of the table. TABLE 13 Pore areas forvarious macrocyclic modules (Å²) HEXAMER HEXAMER SYNTHON B QM MMTrans-1,2- imine (trans) imine (trans) cyclohexane 23.5 Å² 25.4 ± 4.9 Å²Endo-endo-1,3- imine (trans) imine (trans) bicycloheptane 30.1 Å² 30.0 ±3.6 Å²

[0379] An example of the energy-minimized conformations of some hexamermacrocyclic modules having groups of substituents are shown in FIGS. 19Aand 19B. Referring to FIG. 19A, a Hexamer 1-h-(OH)₃ is shown having agroup of —OH substituents. Referring to FIG. 19B, a Hexamer 1-h-(OEt)₃is shown having a group of —OEt substituents. The differences in porestructure and area between these two examples, which also reflectconformational and flexibility differences, are evident. Thismacrocyclic module results in a composition which may be used toregulate pores. Selection of ethoxy synthon substituents over hydroxysynthon substituents for this hexamer composition is a method which maybe used for transporting selected species.

[0380] The pore size of macrocyclic modules was determinedexperimentally using a voltage-clamped bilayer procedure. A quantity ofa macrocyclic module was inserted into a lipid bilayer formed byphosphatidylcholine and phosphatidylethanolamine. On one side of thebilayer was placed a solution containing the cationic species to betested. On the other side was a solution containing a reference cationicspecies known to be able to pass through the pore of the macrocyclicmodule. Anions required for charge balance were selected which could notpass through the pores of the macrocyclic module. When a positiveelectrical potential was applied to the solution on the side of thelipid bilayer containing the test species, if the test species passedthrough the pores in the macrocyclic modules, a current was detected.The voltage was then reversed to detect current due to transport of thereference species through the pores, thereby confirming that the bilayeris a barrier to transport and that the pores of the macrocyclic modulesprovide transport of species.

[0381] Using the above technique, a hexameric macrocyclic modulecomprised of 1R,2R-(−)-transdiaminocyclohexane and2,6-diformal-4-(1-dodec-1-ynyl)phenol synthons, having imine groups asthe linkages (the first module in Table 1) was tested for transport ofvarious ionic species. The results are shown in Table 14. TABLE 14Voltage-clamped bilayer test for macrocyclic module pore size CalculatedCalculated van der van der Waals Waals Does ionic radius of radius ofionic species ionic species with one pass through Ionic species species(Å) water shell (Å) pore? Na⁺ 1.0 2.2 Yes K⁺ 1.3 2.7 Yes Ca²⁺ 1.0 2.7Yes NH₄ ⁺ 1.9 2.9 Yes Cs⁺ 1.7 3.0 Yes MeNH₃ ⁺ 2.0 3.0 Yes EtNH₃ ⁺ 2.63.6 No NMe₄ ⁺ 2.6 3.6 No Aminoguanidinium 3.1 4.1 No NEt₄ ⁺ 3.9 4.4 NoCholine 3.8 4.8 No Glucosamine 4.2 5.2 No

[0382] The results in Table 14 show that the cut-off for passage throughthe pore in the selected module is a van der Waals radius of between 2.0and 2.6 Å. In Table 12, the QM and MM computed pore sizes are given asareas. Using the equation for area of a circle, A=πr², the computed areaof the pore in the first module of Table 12, 14.3 Å², gives a value forr of 2.13 Å. Ions having van der Waals radii of less than 2.13 Åwould beexpected to traverse the pore and those with larger radii would not, andthat is what was observed. CH₃NH₃ ⁺, having a radius of 2.0 Å, passedthrough the pore while CH₃CH₂NH₃ ⁺, with a radius of 2.6 Å, did not.Without being held to a particular theory, and recognizing that severalfactors influence pore transport, the observed ability of hydrated ionsto pass through the pore may be due to partial dehydration of thespecies to enter the pore, transport of water molecules and ions throughthe pore separately or with reduced interaction during transport, andrecoordination of water molecules and ions after transport. The detailsof pore structure, composition, and chemistry, the flexibility of themacrocyclic module, and other interactions may affect the transportprocess.

Example 23

[0383] Pore properties of 1,2-imine-linked and 1,2-amine-linked hexamermacrocyclic modules are illustrated in Table 15. Referring to Table 15,the bilayer clamp data indicates that the passage and exclusion ofcertain species through the pore of the modules correlates with thecomputational size of the pores. Further, these surprising data showthat a very small change in the placement of atoms and/or structuralfeatures can lead to a discrete change in transport properties and allowregulation of transport through the pore by variation of synthons andlinkages, among other factors. TABLE 15 Voltage-clamped bilayer test formacrocyclic module pore size Radius of solute with H₂O (radius of 2^(nd)hydration Hexamer 1a Hexamer 1jh Solute Radius of shell in (1,2-imine)(1,2-amine) species Solute parentheses) Radius = 3.3 Å Radius = 3.9 ÅLi⁺ 0.6 2.0 (5.6) No Yes Na⁺ 1.0 2.2 Yes Yes K⁺ 1.3 2.7 Yes Yes Ca⁺ 1.02.7 Yes Yes Mg²⁺ 0.7 2.8 (5.5) No Yes NH₄ ⁺ 1.9 2.9 Yes Yes Cs⁺ 1.7 3Yes Yes MeNH₃ ⁺ 2 3 Yes Yes EtNH₃ ⁺ 2.6 3.6 No Yes NMe₄ ⁺ 2.6 3.6 No YesAminoguanidine 3.1 4.1 No Yes Choline 3.8 4.8 No Yes NEt₄ ⁺ 3.9 4.4 NoNo Glucosamine 4.2 5.2 No No NPr₄ ⁺ — — — No

Example 24

[0384] The filtration function of a membrane may be described in termsof its solute rejection profile. The filtration function of somenanofilm membranes is exemplified in Tables 16-17. TABLE 16 Examplefiltration function of a G-membrane MOLECULAR SOLUTE WEIGHT PASS/NO PASSAlbumin 68 kDa NP Ovalbumin 44 kDa P Myoglobin 17 kDa P β₂-Microglobulin12 kDa P Insulin 5.2 kDa P Vitamin B₁₂ 1350 Da P Urea, H₂O, ions <1000Da P

[0385] TABLE 17 Example filtration function of a T-membrane MOLECULARSOLUTE WEIGHT PASS/NO PASS β₂-Microglobulin 12 kDa NP Insulin 5.2 kDa NPVitamin B₁₂ 1350 Da NP Glucose 180 Da NP Creatinine 131 Da NP H₂PO₄ ⁻,HPO₄ ²⁻ ≈97 Da NP HCO₃ 61 Da NP Urea 60 Da NP K+ 39 Da P Na+ 23 Da P

[0386] The passage or exclusion of a solute is measured by itsclearance, which reflects the portion of solute that actually passesthrough the membrane. The no pass symbol in Tables 16-17 indicates thatthe solute is partly excluded by the nanofilm, sometimes less than 90%rejection, often at least 90% rejection, sometimes at least 98%rejection. The pass symbol indicates that the solute is partly clearedby the nanofilm, sometimes less than 90% clearance, often at least 90%clearance, sometimes at least 98% clearance.

Example 25

[0387] Selective filtration and relative clearance of solutes isexemplified in Table 18. In Table 18, the heading “high permeability”indicates a clearance of greater than about 70-90% of the solute. Theheading “medium permeability” indicates a clearance of less than about50-70% of the solute. The heading “low permeability” indicates aclearance of less than about 10-30% of the solute. TABLE 18 Clearance ofsolutes by nanofilms Nanofilm high permeability medium permeability lowpermeability Hexamer 1a H₂O, Na⁺, K⁺, Cs⁺ Ca²⁺, Mg²⁺, phosphate Glucose,Li⁺, urea, creatinine water H₂O Glucose, Na⁺, K⁺, Ca²⁺, Mg²⁺, Li⁺, urea,nanofilm phosphate creatinine ion H₂O, Na⁺, K⁺, phosphate Glucose Ca²⁺,Mg²⁺, Li⁺, urea, nanofilm creatinine glucose H₂O, Na⁺, K⁺, GlucosePhosphate Ca²⁺, Mg²⁺, Li⁺, urea, nanofilm creatinine G H₂O, Na⁺, K⁺,phosphate, Vitamin B₁₂, Insulin, β₂ Myglobin, Ovalbumin, nanofilmGlucose, Ca²⁺, Mg²⁺, Li⁺, Microglobulin Albumin, urea, creatinine gasHe, H₂ — H₂O and larger, liquids in nanofilm general anion Cl⁻ HCO₃ ⁻,Phosphate — nanofilm

Example 26

[0388] The approximate diameter of various species to be considered in afiltration process are illustrated in Table 19: solute molecular weight(Da) diameter (Å) virus 10⁶ 133  immunoglobulin G (IgG) 10⁵ 60 albumin50 × 10⁴ 50 β₂-Microglobulin 10³ 13 urea 60  — Na⁺ 23  —

[0389] Synthon and Macrocyclic Module Syntbesis Methods

[0390] All chemical structures illustrated and described in thisspecification, both in the description above and the examples below, aswell as in the figures, are intended to encompass and include allvariations and isomers of the structure which are foreseeable, includingall stereoisomers and constitutional or configurational isomers when theillustration, description, or figure is not explicitly limited to anyparticular isomer.

[0391] Methods for Preparing Cyclic Synthons

[0392] To avoid the need to separate single configurational orenantiomeric isomers from complex mixtures resulting from non-specificreactions, stereospecific or at least stereoselective coupling reactionsmay be employed in the preparation of the synthons of this invention.The following are examples of synthetic schemes for severa classes ofsynthons useful in the preparation of macrocyclic modules of thisinvention. In general, the core synthons are illustrated, and lipophilicmoieties are not shown on the structures, however, it is understood thatall of the following synthetic schemes might encompass additionallipophilic or hydrophilic moieties used to prepare amphiphilic and othermodified macrocyclic modules. Species are numbered in relation to thescheme in which they appear; for example, “S1-1” refers to the structure1 in Scheme 1.

[0393] An approach to preparing synthons of 1,3-Diaminocyclohex-5-ene isshown in Scheme 1. Enzymatically assisted partial hydrolysis of the

[0394] symmetrical diester S1-1 is used to give enantiomerically pureS1-2. S1-2 is subjected to the Curtius reaction and then quenched withbenzyl alcohol to give protected amino acid S1-3. lodolactonization ofcarboxylic acid S1-4 followed by dehyrohalogenation gives unsaturatedlactone S1-6. Opening of the lactone ring with sodium methoxide givesalcohol S1-7, which is converted with inversion of configuration to S1-8in a one-pot reaction involving mesylation, SN₂ displacement with azide,reduction and protection of the resulting amine with di-tert-butyldicarbonate. Epimerization of S1-8 to the more stable diequatorialconfiguration followed by saponification gives carboxylic acid S1-10.S1-10 is subjected to the Curtius reaction. A mixed anhydride isprepared using ethyl chlorofornate followed by reaction with aqueousNaN₃ to give the acyl azide, which is thermally rearranged to theisocyanate in refluxing benzene. The isocyanate is quenched with2-trimethylsilylethanol to give differentially protected tricarbamateS1-11. Reaction with trifluoroacetic acid (TFA) selectively deprotectsthe 1,3-diamino groups to provide the desired synthon S1-12.

[0395] In another variation, an approach to preparing synthons of1,3-Diaminocyclohexane is shown in Scheme 1a.

[0396] Some aspects of these preparations are given in Suami et al., J.Org. Chem. 1975, 40, 456 and Kavadias et al. Can. J. Chem. 1978, 56,404.

[0397] In another variation, an approach to preparing synthons of1,3-substituted cyclohexane is shown in Scheme 1b.

[0398] This synthon will remain “Z-protected” until the macrocyclicmodule has been cyclized. Subsequent deprotection to yield a macrocyclicmodule with amine functional groups is done by a hydrogenation protocol.

[0399] Norbomanes (bicycloheptanes) may be used to prepare synthons ofthis invention, and stereochemically controlled multifunctionalizationof norbomanes can be achieved. For example, Diels-Alder cycloadditionmay be used to form norbornanes incorporating various functional groupshaving specific, predictable stereochemistry. Enantiomerically enhancedproducts may also be obtained through the use of appropriate reagents,thus limiting the need for chiral separations.

[0400] An approach to preparing synthons of 1,2-Diaminonorbomane isshown in Scheme 2.

[0401] 5-(Benzyloxy-methyl)-1,3-cyclopentadiene (S2-13) is reacted withdiethylaluminum chloride Lewis acid complex of di-(l)-menthyl fumarate(S2-14) at low temperature to give the diastereomerically pure norbomeneS2-15. Saponification with potassium hydroxide in aqueous ethanol givesthe diacid S2-16, which is subjected to a tandem Curtius reaction withdiphenylphosphoryl azide (DPPA), the reaction product is quenched with2-trimethylsilylethanol to give the biscarbamate S2-17. Deprotectionwith TFA gives diamine S2-18.

[0402] Another approach to this synthon class is outlined in Scheme 3.Opening of anhydride S3-19 with methanol in the presence of quinidinegives the enantiomerically pure ester acid S3-20. Epimerization of theester group with sodium methoxide (NaOMe) gives S3-21. A Curtiusreaction with DPPA followed by quenching with trimethylsilylethanolgives carbamate S3-22. Saponification with NaOH gives the acid S3-23,which undergoes a Curtius reaction,

[0403] than quenched with benzyl alcohol to give differentiallyprotected biscarbamate S3-24. Compound S3-24 can be fully deprotected toprovide the diamine or either of the carbamates can be selectivelydeprotected.

[0404] An approach to preparing synthons ofendo,endo-1,3-Diaminonorbomane is shown in Scheme 4.5-Trimethylsilyl-1,3-cyclopentadiene (S4-25) is reacted with thediethylaluminum chloride Lewis acid complex of di-(l)-menthyl fumarateat low temperature to give nearly diastereomerically pure norbomeneS4-26. Crystallization of S4-26 from alcohol results in recovery ofgreater than 99% of the single diastereomer. Bromolactonization followedby silver mediated rearrangement gives mixed diester S4-28 with analcohol moiety at the 7-position. Protection of the alcohol with benzylbromide and selective deprotection of the methyl ester gives the freecarboxylic acid S4-30. A Curtius reaction results in trimethylsilylethylcarbamate norbomene S4-31. Biscarbonylation of the olefin in methanol,followed by a single-step deprotection and dehydration gives themono-anhydride S4-33. Quinidine mediated opening of the anhydride withmethanol gives S4-34. Curtius transformation of S4-34 gives thebiscarbamate S4-35, which is deprotected with TFA or tetrabutylammoniumfluoride (TBAF) to give diamine S4-36.

[0405] Another approach to this class of synthons is outlined in Scheme5. Benzyl alcohol opening of S3-19 in the presence of quinidine givesS5-37 in high enantiomeric excess. lodolactonization followed by NaBH₄reduction gives lactone S5-39. Treatment with NaOMe liberates the methylester and the free alcohol to generate S5-40. Transformation of thealcohol S5-40 to the inverted t-butyl carbamate protected amine S5-41 isaccomplished in a one-pot reaction by azide deplacement of the mesylateS5-40 follwed by reduction to the amine, which is protected withdi-tert-butyl dicarbonate. Hydrogenolytic cleavage of the benzyl esterand epimerization of the methyl ester to the exo configuration isfollowed by protection of the free acid with benzyl breomide to giveS5-44. Saponification of the methyl ester followed by atrimethylsilylethanol quenched Curtius reaction

[0406] gives biscarbamate S5-46, which is cleaved with TFA to give thedesired diamine S5-47.

[0407] An approach to preparing synthons ofexo,endo-1,3-Diaminonorbornane is shown in Scheme 6. p-Methoxybenzylalcohol opening of norbomene anhydride S3-19 in presence of quinidinegives monoester S6-48 in high enantiomeric excess. Curtius reaction ofthe free acid gives protected all endo monoacid-monoamine S6-49.Biscarbonylation and anhydride formation gives exo-monoanhydride S6-51.Selective methanolysis in the presence of quinine gives S6-52. Atrimethylsiylethanol quenched Curtius reaction gives biscarbamate S6-53.Epimerization of the two esters results in the more sterically stableS6-54. Cleavage of the carbamate groups provides synthon S6-55.

[0408] Methods to Prepare Macrocyclic Modules

[0409] Synthons may be coupled to one another to form macrocyclicmodules. In one variation, the coupling of synthons may be accomplishedin a concerted scheme. Preparation of a macrocyclic module by theconcerted route may be performed using, for example, at least two typesof synthons, each type having at least two functional groups forcoupling to other synthons. The functional groups may be selected sothat a functional group of one type of synthon can couple only to afunctional group of the other type of synthon. When two types ofsynthons are used, a macrocyclic module may be formed having alternatingsynthons of different types. Scheme 7 illustrates a concerted modulesynthesis.

[0410] Referring to Scheme 7,1,2-Diaminocyclohexane, S7-1, is a synthonhaving two amino functional groups for coupling to other synthons, and2,6-diformyl-4-dodec-1-ynylphenol, S7-2, is a synthon having two formylgroups for coupling to other synthons. An amino group may couple with aformyl group to form an imine linkage. In Scheme 7, a concerted producthexamer macrocyclic module is shown.

[0411] In one variation, a mixture of tetramer, hexamer, and octamermacrocyclic modules may be formed in the concerted scheme. The yields ofthese macrocyclic modules can be varied by changing the concentration ofvarious synthons in the reagent mixture, and among other factors, bychanging the solvent, temperature, and reaction time.

[0412] The imine groups of S7-3 can be reduced, e.g. with sodiumborohydride, to give amine linkages. If the reaction is carried outusing 2,6-di(chlorocarbonyl)-4-dodec-1-ynylphenol instead of2,6-diformyl-4-dodec-1-ynylphenol, the resulting module will containamide linkages. Similarly, if 1,2-dihydroxycyclohexane is reacted with2,6-di(chlorocarbonyl)-4-dodec-1-ynylphenol, the resulting module willcontain ester linkages.

[0413] In some variations, the coupling of synthons may be accomplishedin a stepwise scheme. In an example of the stepwise preparation ofmacrocyclic modules, a first type of synthon is substituted with oneprotected functional group and one unprotected functional group. Asecond type of synthon is substituted with an unprotected functionalgroup that will couple with the unprotected functional group on thefirst synthon. The product of contacting the first type of synthon withthe second type of synthon may be a dimer, which is made of two coupledsynthons. The second synthon may also be substituted with anotherfunctional group which is either protected, or which does not couplewith the first synthon when the dimer is formed. The dimer may beisolated and purified, or the preparation may proceed as a one-potmethod. The dimer may be contacted with a third synthon having twofunctional groups, only one of which may couple with the remainingfunctional group of either the first or second synthons to form atrimer, which is made of three coupled synthons. Such stepwise couplingof synthons may be repeated to form macrocyclic modules of various ringsizes. To cyclize or close the ring of the macrocyclic module, then^(th) synthon which was coupled to the product may be substituted witha second functional group which may couple with the second functionalgroup of a previously coupled synthon that has not been coupled, whichmay be deprotected for that step. The stepwise method may be carried outwith synthons on solid phase support. Scheme 8 illustrates a stepwisepreparation of module SC8-1.

[0414] Compound S8-2 is reacted with S8-3, in which the phenol isprotected as the benzyl ether and the nitrogen is shown as protectedwith a group “P,” which can be any of a large number of protectinggroups well-known in the art, in the presence of methanesulfonylchloride (Endo, K.; Takahashi, H. Heterocycles, 1999, 51, 337), to giveS8-4. Removal of the N-protecting group give the free amine S8-5, whichcan be coupled with synthon S8-6 using any standard peptide couplingreaction such as BOP/HOBt to give S8-7. Deprotection/coupling isrepeated, alternating synthons S8-3 and S8-6 until a linear constructwith eight residues is obtained. The remaining acid and amine protectinggroups on the 8-mer are removed and the oligomer is cyclized, see e.g.,Caba, J. M., et al., J. Org. Chem., 2001, 66:7568 (PyAOP cyclization)and Tarver, J. E. et al., J. Org. Chem., 2001, 66:7575 (active estercyclization). The R group is H or an alkyl group linked via a functionalgroup to the benzene ring, and X is N, O, or S. Examples of solidsupports include Wang resin, hydrogels, silica gels, sepharose,sephadex, agarose, and inorganic solids. Using a solid support mightsimplify the procedure by obviating purification of intermediates alongthe way. The final cyclization may be done in a solid phase mode. A“safety-catch linker” approach (Bourne, G. T., et al., J. Org. Chem.,2001, 66:7706) may be used to obtain cyclization and resin cleavage in asingle operation.

[0415] In another variation, a concerted method involves contacting twoor more different synthons and a linker molecule as shown in Scheme 9,where R may be an alkyl group or other lipophilic group.

[0416] In another variation, a stepwise linear method involves varioussynthons and a soil phase support as shown in Scheme 10.

[0417] In another variation, a stepwise convergent method involvessynthon trimers and a solid phase support as shown in Scheme 11. Thismethod can also be done without the solid phase support using trimers insolution.

[0418] In another variation, a template method involves synthons broughttogether by a template as shown in Scheme 12. Some aspects of thisapproach (and an Mg2+ template) are given in Dutta et al. Inorg. Chem.1998, 37, 5029.

[0419] In another variation, a linker molecule method involves cyclizingsynthons in solution as shown in Scheme 13.

[0420] Reagents for the following examples were obtained from AldrichChemical Company and VWR Scientific Products. All reactions were carriedout under nitrogen or argon atmosphere unless otherwise noted. Solventextracts of aqueous solutions were dried over anhydrous Na₂SO₄.Solutions were concentrated under reduced pressure using a rotaryevaporator. Thin layer chromatography (TLC) was done on Analtech Silicagel GF (0.25 mm) plates or on Machery-Nagel Alugram Sil G/UV (0.20 mm)plates. Chromatograms were visualized with either UV light,phosphomolybdic acid, or KMnO₄. All compounds reported were homogenousby TLC unless otherwise noted. HPLC analyses were performed on a HewlettPackard 1100 system using a reverse phase C-18 silica column.Enantiomeric excess was determined by HPLC using a reverse phase(l)-leucine silica column from Regis Technologies. All ¹[H] and ¹³[C]NMR spectra were collected at 400 MHz on a Varian Mercury system.Electrospray mass spectra were obtained by Synpep Corp., or on a ThermoFinnigan LC-MS system.

Example 27

[0421] 2,6-Diformyl-4-bromophenol

[0422] Hexamethylenetetramine (73.84 g, 526 mmol) was added to TFA (240mL) with stirring. 4-Bromophenol (22.74 g, 131 mmol) was added in oneportion and the solution heated in an oil bath to 120° C. and stirredunder argon for 48 h. The reaction mixture was then cooled to ambienttemperature. Water (160 mL) and 50% aqueous H₂SO₄ (80 mL) were added andthe solution stirred for an additional 2 h. The reaction mixture waspoured into water (1600 mL) and the resulting precipitate collected on aBuichner funnel. The precipitate was dissolved in ethyl acetate (EtOAc)and the solution was dried over MgSO₄. The solution was filtered and thesolvent removed on a rotary evaporator. Purification by columnchromatography on silica gel (400 g) using a gradient of 15-40% ethylacetate in hexanes resulted in a isolation of the product as a yellowsolid (18.0 g, 60%).

[0423]¹H NMR (400 MHz, CDCl₃) δ 11.54 (s, 1 H, OH), 10.19 (s, 2 H, CHO),8.08 (s, 2 H, ArH).

Example 28

[0424] 2,6-Diformyl-4-(dodecyn-1-yl)phenol

[0425] 2,6-Diformyl-4-bromophenol (2.50 g, 10.9 mmol), 1-dodecyne (2.00g, 12.0 mmol), CuI (65 mg, 0.33 mmol), andbis(triphenylphosphine)palladium)II) dichloride were suspended indegassed acetonitrile (MeCN) (5 mL) and degassed benzene (1 mL). Theyellow suspension was sparged with argon for 30 min and degassed Et₃N (1mL) was added. The resulting brown suspension was sealed in a pressurevial, warmed to 80° C. and held there for 12 h. The mixture was thenpartitioned between EtOAc and KHSO₄ solution. The organic layer wasseparated, washed with brine, dried (MgSO₄) and concentrated underreduced pressure. The dark yellow oil was purified by columnchromatography on silica gel (25% Et₂O in hexanes) to give 1.56 g (46%)of the title compound.

[0426]¹H NMR (400 MHz, CDCl₃) δ11.64 (s, 1 H, OH), 10.19 (s, 2 H, CHO),7.97 (s, 2 H, ArH), 2.39 (t, 2 H, J=7.2 Hz, propargylic), 1.59 (m, 3 H,aliphatic), 1.43, (m, 2 H, aliphatic), 1.28 (m, 11 H, aliphatic), 0.88(t, 3 H, J=7.0 Hz, CH₃).

[0427]¹³C NMR (400 MHz, CDCl₃) δ 192.5, 162.4, 140.3, 122.8, 116.7,91.4, 77.5 31.9 29.6, 29.5, 29.3, 29.1, 28.9, 28.5, 22.7, 19.2, 14.1.

[0428] MS (FAB): Calcd. for C₂₀H₂₇O₃ 315.1960; found 315.1958 [M+H]⁺.

Example 29

[0429] 2,6-Diformyl-4-(dodecen-1-yl)phenol

[0430] 2,6-Diformyl-4-bromophenol (1.00 g, 4.37 mmol), 1-dodecene (4.8mL, 21.7 mmol), 1.40 g tetrabutylammonium bromide (4.34 mmol), 0.50 gNaHCO₃ (5.95 mmol), 1.00 g LiCl (23.6 mmol) and 0.100 g palladiumdiacetate (Pd(OAc)₂) (0.45 mmol) were combined in 30 mL degassedanhydrous dimethylformamide (DMF). The mixture was sparged with argonfor 10 min and then sealed in a pressure vial which was warmed to 82° C.and held for 40 h. The crude reaction mixture was partitioned betweenCH₂Cl₂ and 0.1 M HCl solution. The organic layer was washed with 0.1 MHCl (2×), brine (2×), and saturated aqueous NaHCO₃ (2×), dried overMgSO₄ and concentrated under reduced pressure. The dark yellow oil waspurified by column chromatography on silica gel (25% hexanes in Et₂O) togive 0.700 g (51%) of the title compound as primarily the Z isomer.

[0431]¹H NMR (400 MHz, CDCl₃) δ11.50 (s, 1 H, OH), 10.21 (s, 2 H, CHO),7.95 (s, 2 H, ArH), 6.38 (d, 1 H, vinyl), 6.25 (m, 1 H, vinyl), 2.21 (m,2 H, allylic), 1.30-1.61 (m, 16 H, aliphatic), 0.95 (t, 3 H, J=7.0 Hz,CH₃).

[0432] MS (FAB): Calcd. for C₂₀H₂₇O₃ 315.20; found 315.35 [M−H]⁻.

Example 30

[0433] (1R,6S)-6-Methoxycarbonyl-3-cyclohexene-1-carboxylic Acid (S1-2)

[0434] S1-1 (15.0 g, 75.7 mmol) was suspended in pH 7 phosphate buffer(950 mL). Pig liver esterase (2909 units) was added, and the mixturestirred at ambient temperature for 72 h with the pH maintained at 7 byaddition of 2M NaOH. The reaction mixture was washed with ethyl acetate(200 mL), acidified to pH 2 with 2M HCl, and extracted with ethylacetate (3×200 mL). The extracts were combined, dried, and evaporated toafford 13.8 g (99%) of S1-2.

[0435]¹H NMR: (CDCl₃) δ 2.32 (dt, 2 H, 2_(ax)- and 5_(ax)-H's), 2.55(dt, 2 H, ² _(eq)- and 5_(eq)-H's), 3.00 (m, 2 H, 1- and 6-H's), 3.62(s, 3 H, CO₂Me), 5.61 (m, 2 H, 3- and 4-H's).

Example 31

[0436] Methyl (1S, 6R)-6-Benzyloxycarbonylaminocyclohex-3-enecarboxylate(S1-3)

[0437] S1-2 (10.0 g, 54.3 mmol) was dissolved in benzene (100 mL) underN₂. Triethylamine (13.2 g, 18.2 mL, 130.3 mmol) was added followed byDPPA (14.9 g, 11.7 mL, 54.3 mmol). The solution was refluxed for 20 h.Benzyl alcohol (5.9 g, 5.6 mL, 54.3 mmol) was added and reflux continuedfor 20 h. The solution was diluted with EtOAc (200 mL), washed withsaturated aqueous NaHCO₃ (2×50 mL), water (20 mL), and saturated aqueousNaCl (20 mL), dried and evaporated to give 13.7 g (87%) of S1-3.

[0438]¹H NMR: (CDCl₃) δ 2.19 (dt, 1 H, 5_(ax)-H), 2.37 (tt, 2 H, 2_(ax)-and 5_(eq)-H's), 2.54 (dt, 1 H, 2_(eq)-H), 2.82 (m, 1 H, 1-H), 3.65 (s,3 H, CO₂Me), 4.28 (m, 1 H, 6-H), 5.08 (dd, 2 H, CH₂Ar), 5.42 (d, 1 H,NH), 5.62 (ddt, 2 H, 3- and 4-H's), 7.35 (mn, 5 H, Ar H's).

Example 32

[0439] (1S, 6R)-6-Benzyloxycarbonylaminocyclohex-3-enecarboxylic acid(S1-4)

[0440] S1-3 (23.5 g, 81.3 mmol) was dissolved in MeOH (150 mL) and thesolution cooled to 0° C. 2M NaOH (204 mL, 0.41 mol) was added, themixture allowed to come to ambient temperature and then it was stirredfor 48 h. The reaction mixture was diluted with water (300 mL),acidified with 2M HCl, and extracted with dichloromethane (250 mL),dried, and evaporated. The residue was recrystallized from diethyl etherto give 21.7 (97%) of S1-4.

[0441]¹H NMR: (CDCl₃) δ 2.20 (d, 1 H, 5_(ax)-H), 2.37 (d, 2 H, 2_(ax)-and 5_(eq)-H's), 2.54 (d, 1 H, ² _(eq)-H), 2.90 (br s, 1 H, 1-H), 4.24(br s, 1 H, 6-H), 5.08 (dd, 2 H, CH₂Ar), 5.48 (d, 1 H, NH), 5.62 (dd, 2H, 3- and 4-H's), 7.35 (m, 5 H, Ar H's).

Example 33

[0442](1S,2R,4R,5R)-2-Benzyloxycarbonylamino-4-iodo-7-oxo-6-oxabicyclo[3.2.1]octane(S1-5)

[0443] S1-4 (13.9 g, 50.5 mmol) was dissolved in dichloromethane (100mL) under N₂, 0.5 M NaHCO₃ (300 mL), KI (50.3 g, 303.3 mmol), and iodine(25.6 g, 101 mmol) were added and the mixture stirred at ambienttemperature for 72 h. The mixture was diluted with dichloromethane (50mL) and the organic phase separated. The organic phase was washed withsaturated aqueous Na₂S₂O₃ (2×50 mL), water (30 mL), and saturatedaqueous NaCl (20 mL), dried and evaporated to afford 16.3 g (80%) ofS1-5.

[0444]¹H NMR: (CDCl₃) δ 2.15 (m, 1 H, 8_(ax)-H), 2.42 (m, 2 H, 3_(ax)-and 8_(eq)-H's), 2.75 (m, 2 H, 1- and 3_(eq)-H's), 4.12 (br s, 1 H,2-H), 4.41 (t, 1 H, 4-H), 4.76 (dd, 1 H, 5-H), 4.92 (d, 1 H, NH), 5.08(dd, 2 H, CH₂Ar), 7.35 (m, 5 H, Ar H's).

Example 34

[0445](1S,2R,5R)-2-Benzyloxycarbonylamino-7-oxo-6-oxabicyclo[3.2.1]oct-3-ene(S1-6).

[0446] S1-5 (4.0 g, 10 mmol) was dissolved in benzene (50 mL) under N₂.1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU) (1.8 g, 12 mmol) was added andthe solution refluxed for 16 h. The precipitate was filtered and thefiltrate was diluted with EtOAc (200 mL). The filtrate was washed with1M HCl (20 mL), saturated aqueous Na₂S₂O₃ (20 mL), water (20 mL), andsaturated aqueous NaCl (20 mL), dried and evaporated to give 2.2 g (81%)S1-6.

[0447]¹H NMR: (CDCl₃) δ 2.18 (d, 1 H, 8_(ax)-H), 2.39 (m, 1 H,8_(eq)-H), 3.04 (t, 1 H, 1-H), 4.70 (m, 1 H, 5-H), 4.82 (t, 1 H, 2-H),5.15 (dd, 3 H, CH₂Ar and NH), 5.76 (d, 1 H, 4-H), 5.92 (m, 1 H, 3-H),7.36 (s, 5 H, Ar H's).

Example 35

[0448] (1S,2R,5R)-Methyl2-Benzyloxycarbonylamino-5-hydroxycyclohex-3-enecarboxylate (S1-7)

[0449] S1-6 (9.0 g, 33 mmol) was suspended in MeOH (90 mL) and cooled to0° C. NaOMe (2.8 g, 52.7 mmol) was added and the mixture stirred for 3 hduring which time a solution gradually formed. The solution wasneutralized with 2M HCl, diluted with saturated aqueous NaCl (200 mL),and extracted with dichloromethane (2×100 mL). The extracts werecombined, washed with water (20 mL) and saturated aqueous NaCl (20 ml),dried, and evaporated. The residue was flash chromatographed (silica gel(250 g), 50:50 hexane/EtOAc) to give 8.5 g (85%) of S1-7.

[0450]¹H NMR: (CDCl₃) δ 1.90 (m, 1 H, 6_(ax)-H), 2.09 (m, 1 H,6_(eq)-H), 2.81 (m, 1 H, 1-H), 3.55 (s, 3 H, CO₂Me), 4.15 (m, 1 H, 5-H),4.48 (t, 1 H, 2-H), 5.02 (dd, 2 H, CH₂Ar), 5.32 (d, 1 H, NH), 5.64 (dt,1 H, 4-H), 5.82 (dt, 1 H, 3-H), 7.28 (s, 5 H, Ar H's).

Example 36

[0451] (1S,2R,5S)-Methyl2-Benzyloxycarbonylamino-5-t-butoxycarbonylaminocyclohex-3-enecarboxylate(S1-8).

[0452] S1-7 (7.9 g, 25.9 mmol) was dissolved in dichloromethane (150 mL)and cooled to 0° C. under N₂. Triethylamine (6.3 g, 8.7 mL, 62.1 mmol)and methanesulfonyl chloride (7.1 g, 62.1 mmol) were added and themixture stirred at 0° C. for 2 h. (n-Bu)₄NN₃ (14.7 g, 51.7 mmol) indichloromethane (50 mL) was added and stirring continued at 0° C. for 3h followed by 15 h at ambient temperature. The mixture was cooled to 0°C. and P(n-Bu)₃ (15.7 g, 19.3 mL, 77.7 mmol) and water (1 mL)were addedand the mixture stirred at ambient temperature for 24 h. Di-tert-butyldicarbonate (17.0 g, 77.7 mmol) was added and stirring continued for 24h. The solvent was removed, the residue dissolved in 2:1 hexane/EtOAc(100 mL), the solution filtered, and evaporated. The residue was flashchromatographed (silica gel (240 g), 67:33 hexane/EtOAc) to give 5.9 g(56%) of S1-8.

[0453]¹H NMR: (CDCl₃) δ 1.40 (s, 9 H, Boc H's), 1.88 (m, 1 H, 6_(ax)-H),2.21 (m, 1 H, 6_(eq)-H), 2.95 (m, 1 H, 1-H), 3.60 (s, 3 H, CO₂Me), 4.15(d, 1 H, Boc NH), 4.50 (m, 2 H, 2- and 5-H's), 5.02 (s, 2 H, CH₂Ar),5.38 (d, 1 H, Z NH), 5.65 (m, 2 H, 3- and 4-H's), 7.30 (s, 5 H, Ar H's).

Example 37

[0454] (1R,2R,5S)-Methyl2-Benzyloxycarbonylamino-5-t-butoxycarbonylaminocyclohex-3-enecarboxylate(S1-9)

[0455] S1-8 (1.1 g, 2.7 mmol) was suspended in MeOH (50 mL). NaOMe (0.73g, 13.6 mmol) was added and the mixture refluxed for 18 h after which0.5 M NH₄Cl (50 mL) was added and the resulting precipitate collected.The filtrate was evaporated and the residue triturated with water (25mL). The insoluble portion was collected and combined with the originalprecipitate to give 0.85 g (77%) of S1-9.

[0456]¹H NMR: (CDCl₃) δ 1.38 (s, 9 H, Boc H's), 1.66 (m, 1 H, 6_(ax)-H),2.22 (d, 1 H, 6_(eq)-H), 2.58 (t, 1 H, 1-H), 3.59 (3, 3 H, CO₂Me), 4.22(br s, 1 H, Boc NH), 4.50 (m, 2 H, 2- and 5-H's), 4.75 (d, 1 H, Z NH),5.02 (s, 2 H, CH₂Ar), 5.62 (s, 2 H, 3- and 4-H's), 7.30 (s, 5 H, ArH's).

Example 38

[0457](1R,2R,5S)-2-Benzyloxycarbonylamino-5-t-butoxycarbonylaminocyclohex-3-enecarboxylicacid (S1-10)

[0458] S1-9 (0.85 g, 2.1 mmol) was suspended in 50:50MeOH/dichloromethane (5 mL) and cooled to 0° C. under N₂ after which 2MNaOH (2.0 mL) was added and the mixture stirred at ambient temperaturefor 16 h. The mixture was acidified with 2M HCl upon which a whiteprecipitate formed. The precipitate was collected, washed with water andhexane, and dried to give 0.74 g (90%) of S1-10.

[0459]¹H NMR: (CD₃OD) δ 1.42 (s, 9 H, Boc H's), 1.66 (m, 1 H, 6_(ax)-H),2.22 (d, 1 H, 6_(eq)-H), 2.65 (t, 1 H, 1-H), 4.18 (m, 1 H, 5-H), 4.45(m, 1 H, 5-H), 5.04 (s, 2 H, CH₂Ar), 5.58 (m, 2 H, 3- and 4-H's), 7.35(s, 5 H, Ar H's).

Example 39

[0460](1R,2R,5S)-2-Benzyloxycarbonylamino-5-t-butoxycarbonylamino-1-(2-trimethylsilyl)ethoxycarbonylaminocyclohex-3-ene(S1-11)

[0461] S1-10 (3.1 g, 7.9 mmol) was dissolved in THF (30 mL) under N₂ andcooled to 0° C. Triethylamine (1.6 g, 2.2 mL, 15.9 mmol) was addedfollowed by ethyl chloroformate (1.3 g, 1.5 mL, 11.8 mmol). The mixturewas stirred at 0° C. for 1 h. A solution of NaN₃ (1.3 g, 19.7 mmol) inwater (10 mL) was added and stirring at 0° C. was continued for 2 h. Thereaction mixture was partitioned between EtOAc (50 mL) and water (50mL). The organic phase was separated, dried, and evaporated. The residuewas dissolved in benzene (50 mL) and refluxed for 2 h.2-Trimethylsilylethanol (1.0 g, 1.2 mL, 8.7 mmol) was added and refluxcontinued for 3 h. The reaction mixture was diluted with EtOAc (200 mL),washed with saturated aqueous NaHCO₃ (50 mL), water (20 mL), andsaturated aqueous NaCl (20 mL), dried and evaporated. The residue wasflash chromatographed (silica gel (100 g), 67:33 hexane/EtOAc) to give3.1 g (77%) of S1-11.

[0462]¹H NMR: (CDCl₃) δ −0.02 (s, 9 H, TMS), 0.90 (t, 3 H, CH₂TMS), 1.40(s, 9 H, Boc H's), 2.38 (m, 1 H, ⁶ _(eq)-H), 3.62 (m, 1 H, 1-H), 4.08(m, 2 H, OCH₂CH₂TMS), 4.18 (m, 1 H), 4.38 (m, 1 H), 4.62 (m, 1 H), 5.07(dd, 2 H, CH₂Ar), 5.18 (m, 1 H), 5.26 (m, 1 H), 5.58 (d, 1 H, olefinicH), 5.64 (d, 2 H, olefinic H), 7.30 (s, 5, Ar H's).

Example 40

[0463] (1R,2R,5S)-2-Benzyloxycarbonylamino-1,5-diaminocyclohex-3-ene(S1-12)

[0464] S1-11 (2.5 g, 4.9 mmol) was added to TFA (10 mL) and the solutionstirred at ambient temperature for 16 h after which the solution wasevaporated. The residue was dissolved in water (20 mL), basified to pH14 with KOH and extracted with dichloromethane (3×50 mL). The extractswere combined, washed with water (20 mL), dried and evaporated to give1.1 g (85%) of S1-12.

[0465]¹H NMR: (CDCl₃) δ 1.30 (m, 1 H, 6_(ax)-H), 2.15 (br d, 1 H,6_(eq)-H), 2.68 (m, 1 H, 1-H), 3.42 (br s, 1 H, 5-H), 3.95 (m, 1 H,2-H), 4.85 (d, 1 H, Z NH), 5.08 (t, 2 H, CH₂Ar), 5.45 (d, 1 H, 4-H),5.62 (d, 1 H, 3-H), 7.32 (s, 5 H, Ar H's). ESCI MS m/e 262 M+1.

Example 41

[0466] Isolation of S1b-2 was accomplished using the followingprocedure: Using Schlenk technique 5.57 g (10.0 mmol) of methyl estercompound, S1b-1, was dissolved in 250 mL of THF. In another flask LiOH(1.21 g, 50.5 mmol) was dissolved in 50 mL water and de-gassed bybubbling N₂ through the solution using a needle for 20 minutes. Thereaction was started transferring the base solution into the flaskcontaining S1b-1 over one minute with rapid stirring. The mixture wasstirred at room temperature and work-up initiated when the startingmaterial S1b-1 was completely consumed (Using a solvent system of 66%EtOAc/33% Hexane and developing with phosphomolybdic acid reagent(Aldrich #31,927-9) the starting material S1b-1 has an Rf of 0.88 andthe product streaks with an Rf of approx. 0.34 to 0.64.). The reactionusually takes 2 days. Work-Up: The THF was removed by vacuum transferuntil about the same volume is left as water added to the reaction, inthis case 50 mL. During this the reaction solution forms a white massthat adheres to the stir bar surrounded by clear yellow solution. As theTHF is being removed a separatory funnel is set up including a funnel topour in the reaction solution and an Erlenmeyer flask is placedunderneath the separatory funnel. Into the Erlenmeyer flask is addedsome anhydrous Na₂SO₄. This apparatus should be set up beforeacidification is started. (It is important to set up the separatoryfunnel and Erlenmeyer flask etc. before acidification of the reactionsolution to enable separation of phases and extraction of the productaway from the acid quickly once the solution attains a pH close to 1. Ifthe separation is not preformed rapidly the Boc functional group will behydrolyzed significantly reducing the yield.) Once the volatiles aresufficiently removed, CH₂Cl₂ (125 mL) and water (65 mL) are added andthe reaction flask cooled in an ice bath. The solution is stirredrapidly and 5 mL aliquots of 1N HCl are added by syringe and thereaction solution tested with pH paper. Acid is added until the spot onthe pH paper shows red (not orange) around the edge indicating a pH is 1to 2 has been achieved (The solution being tested is a mixture of CH₂Cl₂and water so the pH paper will show the accurate measurement at the edgeof the spot and not the center.) and the phases are separated by quicklypouring the solution into the separatory funnel. As the phases separatethe stopcock is turned to release the CH₂Cl₂ phase (bottom) into theErlenmeyer flask and swirl the flask to allow the drying agent to absorbwater in the solution. (At this scale of this procedure 80 mL of 1N HClwas used.) Soon after phase separation the aqueous phase is extractedwith CH₂Cl₂ (2×100 mL), dried over anhydrous Na₂SO₄ and the volatilesremoved to produce 5.37 g/9.91 mmoles of a beautiful white microcrystalsreflecting a 99.1% yield. This product can not be purified bychromatography since that process would also hydrolyze the Bocfunctional group on the column.

[0467]¹H NMR (400 MHz, CDCl₃) δ7.33, 7.25 (5H, m, Ph), 6.30 (1H, d, NH),5.97 (1H, d, NH), 5.10 (2H, m, CH₂Ph), 4.90 (1H, d, NH), 3.92, 3.58,3.49 (1H, m, CHNH), 2.96, 2.48, 2.04, 1.95, 1.63 (1H, m, CH₂CHNH), 1.34(9H, s, CCH₃).

[0468] IR (crystalline, cm⁻¹) 3326 br w, 3066 w, 3033 w, 2975 w, 2940 wsh, 1695 vs, 1506 vs, 1454 m sh, 1391 w, 1367 m, 1300 m sh, 1278 m sh,1236 s, 1213 w sh, 1163 vs, 1100 w, 1053 m, 1020 m, 981 w sh, 910 w, 870m, 846 w, 817 w, 775 w sh, 739 m, 696 m.

Example 42

[0469] Di-(l)-menthylbicyclo[2.2.1]hept-5-ene-7-anti-(trimethylsilyl)-2-endo-3-exo-dicarboxylate(S4-26)

[0470] To a solution of S4-25 (6.09 g, 0.0155 mol) in toluene (100 mL)was added diethylaluminum chloride (8.6 mL of a 1.8 M solution intoluene) at −78° C. under nitrogen and the mixture was stirred for 1hour. To the resulting orange solution was added S2-14 (7.00 g, 0.0466mol) dropwise as a −78° C. solution in toluene (10 mL). The solution waskept at −78° C. for 2 hours, followed by slow warming to roomtemperature overnight. The aluminum reagent was quenched with asaturated solution of ammonium chloride (50 mL). The aqueous layer wasseparated and extracted with methylene chloride (100 mL) which wassubsequently dried over magnesium sulfate. Evaporation of the solventleft a yellow solid that was purified by column chromatography (10%ethyl acetate/hexanes) to give S4-26 as a while solid (7.19 g, 0.0136mol, 87% yield).

[0471]¹H NMR: (CDCl₃) δ −0.09 (s, 9 H, SiMe₃), 0.74-1.95 (multiplets, 36H, menthol), 2.72 (d, 1 H, α-menthyl carbonyl CH), 3.19 (bs, 1 H,bridgehead CH), 3.30 (bs, 1 H, bridgehead CH), 3.40 (t, 1 H, α-menthylcarbonyl CH), 4.48 (d of t, 1 H, α-menthyl ester CH), 4.71 (d of t, 1 H,α-menthyl ester CH), 5.92 (d of d, 1 H, CH═CH), 6.19 (d of d, 1 H,CH═CH).

Example 43

[0472]5-exo-Bromo-3-exo-(l)-menthylcarboxybicyclo[2.2.1]heptane-7-anti-(trimethylsilyl)-2,6-carbolactone(S4-27)

[0473] A solution of bromine (3.61 g, 0.0226 mol) in methylene chloride(20 mL) was added to a stirring solution of S4-26 (4.00 g, 0.00754 mol)in methylene chloride (80 mL). Stirring was continued at roomtemperature overnight. The solution was treated with 5% sodiumthiosulfate (150 mL), and the organic layer separated and dried overmagnesium sulfate. The solvent was evaporated at reduced pressure, andthe crude product purified by column chromatography (5% ethylacetate/hexanes) to give S4-27 as a white solid (3.53 g, 0.00754 mol,99% yield).

[0474]¹H NMR: (CDCl₃) δ −0.19 (s, 9 H, SiMe₃), 0.74-1.91 (multiplets, 18H, menthol), 2.82 (d, 1 H, α-lactone carbonyl CH), 3.14 (bs, 1 H,lactone bridgehead CH), 3.19 (d of d, 1 H, bridgehead CH), 3.29 (t, 1 H,α-menthyl carbonyl CH), 3.80 (d, 1 H, α-lactone ester), 4.74 (d of t, 1H, α-menthyl ester CH), 4.94 (d, 1 H, bromo CH).

Example 44

[0475]Bicyclo[2.2.1]hept-5-ene-7-syn-(hydroxy)-2-exo-methyl-3-endo-(l)-menthyldicarboxylate (S4-28)

[0476] S4-27 (3.00 g, 0.00638 mol) was dissolved in anhydrous methanol(150 mL), silver nitrate (5.40 g, 0.0318 mol) added and the suspensionrefluxed for 3 days. The mixture was cooled, filtered through Celite andthe solvent evaporated to give an oily residue. Purification by columnchromatography gave S4-28 as a light yellow oil (1.72 g, 0.00491 mol,77% yield).

[0477]¹H NMR: (CDCl₃) δ 0.75-2.02 (multiplets, 18 H, menthol), 2.83 (d,1 H, α-menthyl carbonyl CH), 3.03 (bs, 1 H, bridgehead CH), 3.14 (bs, 1H, bridgehead CH), 3.53 (t, 1 H, α-methyl carbonyl CH), 3.76 (s, 3 H,CH₃), 4.62 (d of t, 1 H, α-menthyl ester CH), 5.87 (d of d, 1 H, CH═CH),6.23 (d of d, 1 H, CH═CH).

Example 45

[0478]2-exo-Methyl-3-endo-(l)-menthylbicyclo[2.2.1]hept-5-ene-7-syn-(benzyloxy)dicarboxylate (S4-29)

[0479] Benzyl bromide (1.20 g, 0.0070 mol) and silver oxide (1.62 g,0.0070 mol) were added to a stirring solution of S4-28 (0.490 g, 0.00140mol) in DMF (25 mL). The suspension was stirred overnight and thendiluted with ethyl acetate (100 mL). The solution was washed repeatedlywith water followed by 1 N lithium chloride. The organic layer wasseparated and dried with magnesium sulfate. The solvent was evaporatedunder reduced pressure and the crude product was purified by columnchromatography on silica gel to give S4-29 as an oil (0.220 g, 0.000500mol, 36% yield).

[0480]¹H NMR: (CDCl₃) δ 0.74-2.08 (multiplets, 18 H, menthol), 2.83 (d,1 H, α-menthyl carbonyl CH), 3.18 (bs, 1 H, bridgehead CH), 3.44 (bs, 1H, bridgehead CH), 3.52 (t, 1 H, bridge CH), 3.57 (s, 3 H, CH₃), 3.68(t, 1 H, α-methyl carbonyl CH), 4.42 (d of d, 2 H, benzyl —CH₂—), 4.61(d of t, 1 H, α-menthyl ester CH), 5.89 (d of d, 1 H, CH═CH), 6.22 (d ofd, 1 H, CH═CH), 7.25-7.38 (m, 5 H, C₆H₅).

Example 46

[0481]Bicyclo[2.2.1]hept-5-ene-7-syn-(benzyloxy)-2-exocarboxy-3-endo-(l)-menthylcarboxylate (S4-30)

[0482] S4-29 (0.220 g, 0.00050 mol) was added to a mixture oftetrahydrofuran (1.5 mL), water (0.5 mL), and methanol (0.5 mL).Potassium hydroxide (0.036 g, 0.00065 mol) was added and the solutionstirred at room temperature overnight. The solvent was evaporated underreduced pressure and the residue purified by column chromatography (10%ethyl acetate/hexanes) to give S4-30 (0.050 g, 0.00012 mol, 23% yield).

[0483]¹H NMR: (CDCl₃) δ 0.73-2.01 (multiplets, 18 H, menthol), 2.85 (d,1 H, α-menthyl carbonyl CH), 3.18 (bs, 1 H, bridgehead CH), 3.98 (bs, 1H, bridgehead CH), 3.53 (bs, 1 H, bridge CH), 3.66 (t, 1 H, α-methylcarbonyl CH), 4.44 (d of d, 2 H, benzyl —CH₂—), 4.63 (d of t, 1 H,α-menthyl ester CH), 5.90 (d of d, 1 H, CH═CH), 6.23 (d of d, 1 H,CH═CH), 7.25-7.38 (m, 5 H, C₆H₅).

[0484] Mass Spec: calculated for C₂₆H₃₄O₅ 426.24; found 425.4 (M−1) and851.3 (2M−1).

Example 47

[0485]Bicyclo[2.2.1]hept-5-ene-7-syn-(benzyloxy)-2-exo-(trimethylsilylethoxycarbonyl)-amino-3-endo-(l)-menthylcarboxylate (S4-31)

[0486] To a solution of S4-30 in benzene is added triethylamine anddiphenylphosphoryl azide. The solution is refluxed for 24 hours thencooled to room temperature. Trimethylsilylethanol is added, and thesolution refluxed for an additional 48 hours. The benzene solution ispartitioned between ethyl acetate and 1 M sodium bicarbonate. Theorganic layers are combined, washed with 1 M sodium bicarbonate anddried over sodium sulfate. The solvent is evaporated under reducedpressure to give the crude Curtius reaction product.

Example 48

[0487]Bicyclo[2.2.1]heptane-7-syn-(benzyloxy)-2-exo-(trimethylsilylethoxycarbonyl)-amino-3-endo-(l)-menthyl-5-exo-methyl-6-exo-methyltricarboxylate (S4-32)

[0488] S4-31, dry copper(II) chloride, 10% Pd/C, and dry methanol areadded to a flask with vigorous stirring. After degassing, the flask ischarged with carbon monoxide to a pressure just above 1 atm., which ismaintained for 72 hours. The solids are filtered and the residue workedup in the usual way to afford the biscarbonylation product.

Example 49

[0489]Bicyclo[2.2.1]heptane-7-syn-(benzyloxy)-2-exo-(trimethylsilylethoxycarbonyl)-amino-3-endo-(l)-menthylcarbox-5-exo-6-exo-dicarboxylicanhydride (S4-33)

[0490] A mixture of S4-32, formic acid, and a catalytic amount ofp-toluenesulfonic acid is stirred at 90° C. overnight. Acetic anhydrideis added and the reaction mixture refluxed for 6 hours. Removal of thesolvents and washing with ether gives the desired anhydride.

Example 50

[0491]Bicyclo[2.2.1]heptane-7-syn-(benzyloxy)-2-exo-(trimethylsilylethoxycarbonyl)-amino-3-endo-(l)-menthyl-6-exo-carboxy-5-exo-methyldicarboxylate (S4-33)

[0492] To a solution of S4-32 in equal amounts of toluene and carbontetrachloride is added quinidine. The suspension is cooled to 65° C. andstirred for 1 hour. Three equivalents of methanol are slowly added over30 minutes. The suspension is stirred at −65° C. for 4 days followed byremoval of the solvents under reduced pressure. The resulting whitesolid is partitioned between ethyl acetate and 2M HCl. The quinine isrecovered from the acid layer and S4-33 obtained from the organic layer.

Example 51

[0493]Bicyclo[2.2.1]heptane-7-syn-(benzyloxy)-2-exo-(trimethylsilylethoxycarbonyl)-amino-3-endo-(l)-menthyl-6-exo-(trimethylsilylethoxycarbonyl)amino-5-exo-methyldicarboxylate (S4-35)

[0494] To a solution of S4-34 in benzene is added triethylamine anddiphenylphosphoryl azide. The solution is refluxed for 24 hours. Aftercooling to room temperature, 2-trimethylsilylethanol is added and thesolution refluxed for 48 hours. The benzene solution is partitionedbetween ethyl acetate and 1M sodium bicarbonate. The organic layers arecombined, washed with 1M sodium bicarbonate, and dried over sodiumsulfate. The solvent is evaporated under reduced pressure to give thecrude Curtius reaction product.

Example 52

[0495] endo-Bicyclo[2.2.1]hept-5-ene-2-benzylcarboxylate-3-carboxylicacid (S5-37)

[0496] Compound S3-19 (4.00 g, 0.0244 mol) and quinidine (8.63 g, 0.0266mol) were suspended in equal amounts of toluene (50 mL) and carbontetrachloride (50 mL). The suspension was cooled to −55° C. after whichbenzyl alcohol (7.90 g, 0.0732 mol) was added over 15 minutes. Thereaction mixture became homogenous after 3 hours and was stirred at −55°C. for an additional 96 hours. After removal of the solvents, theresidue was partitioned between ethyl acetate (300 mL) and 2Mhydrochloric acid (100 mL). The organic layer was washed with water(2×50 mL) and saturated aqueous sodium chloride (1×50 mL). Drying overmagnesium sulfate and evaporation of the solvent gave S5-37 (4.17 g,0.0153 mol, 63% yield).

[0497]¹H NMR: (CDCl₃) δ 1.33 (d, 1 H, bridge CH₂), 1.48 (d of t, 1 H,bridge CH₂), 3.18 (bs, 1 H, bridgehead CH), 3.21 (bs, 1 H, bridgeheadCH), 3.33 (t, 2 H, α-acid CH), 4.98 (d of d, 2 H, CH₂Ph), 6.22 (d of d,1 H, CH═CH), 6.29 (d of d, 1 H, CH═CH), 7.30 (m, 5 H, C₆H₅).

Example 53

[0498]2-endo-Benzylcarboxy-6-exo-iodobicyclo[2.2.1]heptane-3,5-carbolactone(S5-38)

[0499] S5-37 (4.10 g, 0.0151 mol) was dissolved in 0.5 M sodiumbicarbonate solution (120 mL) and cooled to 0° C. Potassium iodide (15.0g, 0.090 mol) and iodine (7.66 g, 0.030 mol) were added followed bymethylene chloride (40 mL). The solution was stirred at room temperatureovernight. After dilution with methylene chloride (100 mL), sodiumthiosulfate was added to quench the excess iodine. The organic layer wasseparated and washed with water (100 mL) and sodium chloride solution(100 mL). Drying over magnesium sulfate and evaporation of the solventgave S5-38 (5.44 g, 0.0137 mol, 91% yield).

[0500]¹H NMR: (CDCl₃) δ 1.86 (d of q, 1 H, bridge —CH₂—), 2.47 (d of t,1 H, bridge —CH₂—), 2.83 (d of d, 1 H, α-lactone carbonyl CH), 2.93 (bs,1 H, lactone bridgehead CH), 3.12 (d of d, 1 H, α-benzyl ester CH), 3.29(m, 1 H, bridgehead CH), 4.63 (d, 1 H, α-lactone ester CH), 5.14 (d ofd, 2 H, CH₂Ph), 5.19 (d, 1 H, iodo CH), 7.38 (m, 5 H, C₆H₅).

Example 54

[0501] 2-endo-Benzylcarboxy-bicyclo[2.2.1]heptane-3,5-carbolactone(S5-39)

[0502] S5-38 (0.30 g, 0.75 mmol) was placed in DMSO under N₂, NaBH₄ (85mg, 2.25 mmol) added and the solution stirred at 85° C. for 2 h. Themixture was cooled, diluted with water (50 mL) and extracted withdichloromethane (3×20 mL). The extracts were combined, washed with water(4×15 mL) and saturated aqueous NaCl (10 mL), dried, and evaporated togive 0.14 g (68%) of S5-39.

Example 55

[0503] 5-endo-hydroxybicyclo[2.2.1]heptane-2-endo-benzyl-3-endo-methyldicarboxylate (S5-40)

[0504] Compound S5-39 is dissolved in methanol and sodium methoxideadded with stirring. Removal of the solvent gives S5-40.

Example 56

[0505]Bicyclo[2.2.1]heptane-2-endo-benzyl-3-endo-methyl-5-exo-(t-butoxycarbonyl)-aminodicarboxylate (S5-41)

[0506] In a one-pot reaction S5-40 is converted to the correspondingmesylate with methanesulfonyl chloride, sodium azide added to displacethe mesylate to give exo-azide, which is followed by reduction withtributyl phosphine to give the free amine, which is protected as thet-Boc derivative to give S5-41.

Example 57

[0507]Bicyclo[2.2.1]heptane-2-enadocarboxy-3-exo-methyl-5-exo-(t-butoxycarbonyl)-aminocarboxylate (S5-42)

[0508] The benzyl ether protecting group is removed by catalytichydrogenolysis of S5-41 with 10% Pd/C in methanol at room temperaturefor 6 hours. Filtration of the catalyst and removal of the solventyields crude S5-42.

Example 58

[0509]Bicyclo[2.2.1]heptane-2-endo-carboxy-3-exo-methyl-5-exo-(t-butoxycarbonyl)-aminocarboxylate (S5-43)

[0510] Sodium is dissolved in methanol to generate sodium methoxide.S5-42 is added and the mixture stirred at 62° C. for 16 hr. The mixtureis cooled and acetic acid added with cooling to neutralize the excesssodium methoxide. The mixture is diluted with water and extracted withethyl acetate. The extract is dried and evaporated to give S5-43.

Example 59

[0511]Bicyclo[2.2.1]heptane-2-endo-benzyl-3-exo-methyl-5-exo-(t-butoxycarbonyl)-aminodicarboxylate (S5-44)

[0512] Compound S5-43 is reacted with benzyl bromide and cesiumcarbonate in tetrahydrofuran at room temperature to give benzyl esterS5-44, which is isolated by acid work-up of the crude reaction mixture.

Example 60

[0513]Bicyclo[2.2.1]heptane-2-endo-benzyl-3-exo-carboxy-5-exo-(t-butoxycarbonyl)-aminocarboxylate (S5-45)

[0514] Compound S5-44 is dissolved in methanol and cooled to 0° C. underN₂. 2M NaOH (2 equivalents) is added dropwise, the mixture allowed tocome to ambient temperature and is stirred for 5 h. The solution isdiluted with water, acidified with 2M HCl and extracted with ethylacetate. The extract is washed with water, saturated aqueous NaCl, driedand evaporated to give S5-45.

Example 61

[0515]Bicyclo[2.2.1]heptane-2-endo-benzyl-3-exo-(trimethylsilylethoxycarbonyl)-amino-5-exo-(t-butoxycarbonyl)aminocarboxylate (S5-46)

[0516] To a solution of S5-45 in benzene is added triethylamine anddiphenylphosphoryl azide. The solution is refluxed for 24 hours and thencooled to room temperature. Trimethylsilylethanol is added and thesolution refluxed for 48 hours. The solution is partitioned betweenethyl acetate and 1M sodium bicarbonate. The organic layer is washedwith 1M sodium bicarbonate and dried over sodium sulfate. The solvent isevaporated under reduced pressure to give crude Curtius product S5-46.

Example 62

[0517]endo-Bicyclo[2.2.1]hept-5-ene-2-(4-methoxy)benzylcarboxylate-3-carboxylicacid (S6-48)

[0518] Compound S3-19 and quinidine are suspended in equal amounts oftoluene and carbon tetrachloride and cooled to −55° C. p-Methoxybenzylalcohol is added over 15 minutes and the solution stirred at −55° C. for96 hours. After removal of the solvents, the residue is partitionedbetween ethyl acetate and 2 M hydrochloric acid. The organic layer iswashed with water and saturated aqueous sodium chloride. Drying overmagnesium sulfate and removal of the solvent gives S6-48.

Example 63

[0519]endo-Bicyclo[2.2.1]hept-5-ene-2-(4-methoxy)benzyl-3-(trimethylsilylethoxycarbonyl)aminocarboxylate (S6-49)

[0520] To a solution of S6-48 in benzene is added triethylamine anddiphenylphosphoryl azide. The solution is refluxed for 24 hours, cooledto room temperature, trimethylsilylethanol is added, and the solution isrefluxed for an additional 48 hours. The benzene solution is partitionedbetween ethyl acetate and 1 M sodium bicarbonate. The organic layers arecombined, washed with 1 M sodium bicarbonate, and dried with sodiumsulfate. The solvent is evaporated under reduced pressure to give crudeCurtius product S6-49.

Example 64

[0521]Bicyclo[2.2.1]heptane-2-endo-(4-methoxy)benzyl-3-endo-(trimethylsilylethoxycarbonyl)amino-5-exo-methyl-6-exo-methyltricarboxylate (S6-50).

[0522] S6-49, copper(II) chloride, 10% Pd/C, and dry methanol are addedto a flask with vigorous stirring. After degassing the suspension, theflask is charged with carbon monoxide to a pressure just above 1 atm.The pressure of carbon monoxide is maintained over 72 hours. The solidsare filtered off, and the crude reaction mixture worked up in the usualway to afford S6-50.

Example 65

[0523]Bicyclo[2.2.1]heptane-2-endo-(4-methoxy)benzyl-3-endo-(trimethylsilylethoxycarbonyl)amino-5-exo-6-exo-dicarboxylicanhydride (S6-51).

[0524] S6-50, formic acid, and a catalytic amount of p-toluenesulfonicacid is heated at 90° C. overnight. Acetic anhydride is added to thereaction mixture, and it is refluxed for an additional 6 hours. Removalof the solvents and washing with ether affords S6-51.

Example 66

[0525]Bicyclo[2.2.1]heptane-2-endo-(4-methoxy)benzyl-3-endo-(trimethylsilylethoxycarbonyl)amino-5-exo-carboxy-6-exo-methyldicarboxylate (S6-52).

[0526] To a solution of S6-51 in equal amounts of toluene and carbontetrachloride is added quinine. The suspension is cooled to −65° C. andstirred for 1 hour. Three equivalents of methanol are added slowly over30 minutes. The suspension is stirred at −65° C. for 4 days followed byremoval of the solvents. The resulting white solid is partitionedbetween ethyl acetate and 2 M HCl, with S6-52 worked up from the organiclayer.

Example 67

[0527]Bicyclo[2.2.1]heptane-2-endo-(4-methoxy)benzyl-3-endo-(trimethylsilylethoxycarbonyl)amino-5-exo-(trimethylsilylethoxycarbonyl)amino-6-exo-methyldicarboxylate (S6-53).

[0528] To a solution of S6-52 in benzene is added triethylamine anddiphenylphosphoryl azide. The solution is refluxed for 24 hours thencooled to room temperature. 2-Trimethylsilylethanol is added, and thesolution is refluxed for an additional 48 hours. The benzene solution ispartitioned between ethyl acetate and 1 M sodium bicarbonate. Theorganic layers are combined, washed with 1 M sodium bicarbonate, anddried with sodium sulfate. The solvent is evaporated under reducedpressure to give S6-53.

Example 68

[0529]Bicyclo[2.2.1]heptane-2-exo-(4-methoxy)benzyl-3-endo-(trimethylsilylethoxycarbonyl)amino-5-exo-(trimethylsilylethoxycarbonyl)amino-6-endo-methyldicarboxylate (S6-54).

[0530] To a solution of S6-53 in tetrahydrofuran is carefully addedpotassium tert-butoxide. The basic solution is refluxed for 24 hoursfollowed by addition of acetic acid. Standard extraction methods givethe double epimerized product S6-54.

Example 69

[0531] Preparation of hexamer:

[0532] To 0.300 g (1R, 2R)-(−)-trans-1,2-diaminocyclohexane (2.63 mmol)in 5 mL CH₂Cl₂ at 0° C. was added 0.600 g of 2,6-diformyl-4-bromophenol(2.62 mmol) in 5 mL of CH₂Cl₂. The yellow solution was allowed to warmto room temperature and stirred for 48 hours. The reaction solution wasdecanted, and added to 150 mL of methanol. After standing for 30minutes, the yellow precipitate was collected, washed with methanol, andair-dried (0.580 g; 72% yield).

[0533]¹H NMR (400 MHz, CDCl₃) δ 14.31 (s, 3 H, OH), 8.58 (s, 3 H, CH═N),8.19 (s, 3 H, CH═N), 7.88 (d, 3 H, J=2.0 Hz, ArH), 7.27 (d, 3 H, J=2.0Hz, ArH), 3.30-3.42 (m, 6 H, CH₂—CH—N), 1.41-1.90 (m, 24 H, aliphatic).

[0534] MS (FAB): Calcd for C₄₂H₄₆N₆O₃Br₃ 923.115; found 923.3 [M+H]⁺.

Example 70

[0535] Preparation of hexamer:

[0536] To 0.300 g (1R, 2R)-(−)-trans-1,2-diaminocyclohexane (2.63 mmol)in 6 mL CH₂Cl₂ at 0° C. was added 0.826 g of2,6-diformyl-4-(1-dodec-1-yne)phenol (2.63 mmol) in 6 mL of CH₂Cl₂. Theorange solution was stirred at 0° C. for 1 hour and then allowed to warmto room temperature after which stirring was continued for 16 hours. Thereaction solution was decanted and added to 150 mL of methanol. A stickyyellow solid was obtained after decanting the methanol solution.Chromatographic cleanup of the residue gave a yellow powder.

[0537]¹H NMR (400 MHz, CDCl₃) δ 14.32 (s, 3 H, OH), 8.62 (s, 3 H, CH═N),8.18 (s, 3 H, CH═N), 7.84 (d, 3 H, J=2.0 Hz, ArH), 7.20 (d, 3 H, J=2.0Hz, ArH), 3.30-3.42 (m, 6 H, CH₂—CH—N), 2.25 (t, 6 H, J=7.2 Hz,propargylic), 1.20-1.83(m, 72 H, aliphatic), 0.85 (t, 9 H, J=7.0 Hz,CH₃).

[0538]¹³C NMR (400 MHz, CDCl₃) δ 163.4, 161.8, 155.7, 136.9, 132.7,123.9, 119.0, 113.9, 88.7, 79.7, 75.5, 73.2, 33.6, 33.3, 32.2, 29.8,29.7, 29.6, 29.4, 29.2, 29.1, 24.6, 24.5, 22.9,19.6, 14.4.

[0539] MS (FAB): Calcd for C₇₈H₁₀₉N₆O₃ 1177.856; found: 1177.8 [M+H]⁺.

Example 71

[0540] Preparation of hexamer:

[0541] To 0.240 g of 2,6-diformyl-4-(1-dodecene)phenol (0.76 mmol) in 10mL of benzene was added a 10 mL benzene solution of (1R,2R)-(−)-trans-1,2-diaminocyclohexane (0.087 g, 0.76 mmol). The solutionwas stirred at room temperature for 48 hours shielded from the light.The orange solution was taken to dryness and chromatographed (silica,50/50 acetone/Et₂O) to give a yellow sticky solid (33% yield).

[0542]¹H NMR (400 MHz, CDCl₃) δ 14.12 (s, 3 H, OH), 8.62 (s, 3 H, CH═N),8.40 (s, 3 H, CH═N), 7.82 (d, 3 H, J=2.0 Hz, ArH), 7.28 (d, 3 H, J=2.0Hz, ArH), 6.22 (d, 3 H, vinyl), 6.05 (d, 3 H, vinyl), 3.30-3.42 (m, 6 H,CH₂—CH—N), 1.04-1.98(m, 87 H, aliphatic).

[0543] MS (FAB): Calcd for C₇₈H₁₁₅N₆O₃ 1183.90; found: 1184.6 [M+H]⁺.

Example 72

[0544] Preparation of tetramer:

[0545] Preparation of hexamer:

[0546] Triethylamine (0.50 mL, 3.59 mmol) and (1R,2R)-(−)-trans-1,2-diaminocyclohexane (0.190 g, 1.66 mmol) were combinedin 150 mL EtOAc and purged with N₂ for 5 minutes. To this solution wasadded 0.331 g isophthalolyl chloride (1.66 mmol) dissolved in 100 mLEtOAc dropwise over six hours. The solution was filtered and thefiltrate taken to dryness. TLC (5% methanol/CH₂Cl₂) shows the productmixture to be primarily composed of two macrocyclic compositions.Chromatographic separation (silica, 5% methanol/CH₂Cl₂) gave the abovetetramer (0.020 g, 5% yield) and hexamer (about 10%).

[0547] Tetramer:

[0548]¹H NMR (400 MHz, CDCl₃) δ 7.82 (s, 1 H), 7.60 (br s, 2 H), 7.45(br s, 2 H), 7.18 (br s, 1 H), 3.90 (br s, 2 H), 2.22 (d, 2H), 1.85 (m,4 H), 1.41 (m, 4 H).

[0549] MS (ESI): Calcd for C₂₈H₃₃N₄O₄ 489.25; found 489.4 [M+H]⁺.

[0550] Hexamer:

[0551] MS (ESI): Calcd for C₄₂H₄₉N₆O₆ 733.37; found 733.5 [M+H]⁺.

Example 73

[0552] Preparation of macrocyclic modules from benzene and cyclohexanecyclic synthons:

[0553] To a 5 mL dichloromethane solution of 4-dodecyl-2,6-diformylanisole (24 mg; 0.072 mmol) was added a 5 mL dichloromethane solution of(1R, 2R)-(−)-trans-1,2-diaminocyclohexane (8.5 mg; 0.074 mmol). Thissolution was stirred at room temperature for 16 hours and then added tothe top of a short silica column. Elution with diethyl ether and thenremoval of solvent led to the isolation of 22 mg of an off-white solid.Positive ion electrospray mass spectrometry demonstrated the presence ofthe tetramer (m/z 822, MH+), hexamer (m/z 1232, MH⁺), and the octamer(m/z 1643, MH⁺) in the off-white solid. Calculated molecular weightswere as follows: tetramer+H (C₅₄H₈₅N₄O₂, 821.67); hexamer+H(C₈₁H₁₂₇N₆O₃, 1232.00); octamer+H (C₁₀₈H₁₆₉N₈O₄, 1643.33).

Example 74

[0554]

[0555] Templated Imine Octamer. To a 3 neck 100 mL round bottomed flaskwith stirbar, fitted with condenser and addition funnel under argon,amphiphilic dialdehyde phenol 1 (500 mg, 1.16 mmol) was added. Next,Mg(NO₃)₂. 6 H₂O (148 mg, 0.58 mmol) 2 and Mg(OAc)₂. 4 H₂O (124 mg, 0.58mmol) were successively added. The flask was put under vacuo andbackfilled with argon 3×. Anhydrous methanol was transferred to theflask via syringe under argon and the resulting suspension stirred. Themixture was then refluxed for 10 min affording a homogeneous solution.The reaction was allowed to cool to room temperature under positiveargon pressure. (1R, 2R)-(−)-trans-1,2-diaminocyclohexane 4 was added tothe addition funnel followed by cannula transfer of anhydrous MeOH (11.6mL) under argon. The diamine/MeOH solution was added to the stirredhomogeneous metal template/dialdehyde solution drop wise over a periodof 1 h affording an orange oil. The addition funnel was replaced with aglass stopper and the mixture was refluxed for 3 days. The solvent wasremoved in vacuo affording a yellow crystalline solid that was usedwithout further purification.

[0556] Amine Octamer. To a 50 mL schlenk flask with stirbar under argonImine Octamer (314 mg, 0.14 mmol) was added. Next anhydrous THF (15 mL)and MeOH (6.4 mL) were added via syringe under argon and the suspensionstirred at room temperature. To the homogeneous solution, NaBH₄ (136 mg,3.6 mmol) was added in portions and the mixture stirred at roomtemperature for 12 h. The solution was filtered, followed by addition of19.9 mL H₂O. The pH was adjusted to ca. 2 by addition of 4 M HCl, then6.8 mL of an ethylenediamine tetraaceticacid disodium salt dihydrate(0.13 M in H₂O) was added and the mixture stirred for 5 min. To thesolution, 2.0% ammonium hydroxide was added and stirring continued foran additional 5 min. The solution was extracted with ethyl acetate(3×100 mL) the organic layer separated, dried over Na₂SO₄ and thesolvent removed via rotoevaporation affording a pale yellow solid.Recrystallization from chloroform and hexanes afforded the AmineOctamer. Molecular weight was confirmed by ESIMS M+H=experimental=2058.7m/z, calcd=2058.7 m/z.

Example 75

[0557]

[0558] Hexamer 1j. The two substrates,(−)-R,R-1,2-trans-diaminocyclohexane (0.462 mmol, 0.053 g) and2,6-diformyl-4-hexadecyl benzylphenol carboxylate (0.462 mmol, 0.200 g)were added to a 10 mL vial containing a magnetic stirbar followed by theaddition of 2 mL of CH₂Cl₂. The yellow solution was stirred at roomtemperature. After 24 h the reaction solution was plugged through silicagel with diethyl ether, and the solvent removed via roto-evaporation.(232 mg; 98% yield). ¹H NMR (400 MHz, CDCl₃): δ 14.11 (s, 3 H, OH), 8.67(s, 3 H, CH═N), 8.23 (s, 3 H, CH═N), 7.70 (s, 3 H, ArH), 7.11 (s, 3 H,ArH), 4.05-3.90 (t, 6 H, 3J=6.6 Hz, CH₂C(O)OCH₂(CH₂)₁₄CH₃), 3.44 (s, 6H, CH₂C(O)OCH₂(CH₂)₁₄CH₃), 3.30-3.42 (m, 6 H, CH₂—CH—N), 1.21-1.90 (m,108 H, aliphatic) 0.92-0.86 (t, 9 H, 3J=6.6 Hz. ESIMS (+) Calcd forC₉₆H₁₅₁N₆O₉: 1533; Found: 1534 [M+H]⁺.

[0559] Hexamer 1jh. To a 100 mL pear-shaped flask with magnetic stirbarunder argon, Hexamer 1j (0.387 mmol, 0.594 g) was added and dissolved inTHF:MeOH (7:3, 28:12 mL, respectively). Next, NaBH₄ (2.32 mmol, 0.088 g)was added slowly in portions at room temperature for 6.5 h. The solventwas removed by roto-evaporation, the residue dissolved in 125 mL ethylacetate and washed 3×50 mL of H₂O. The organic layer was separated,dried over Na₂SO₄ and the solvent removed by roto-evaporation. Theresulting residue was recrystallized from CH₂Cl₂ and MeOH affording awhite solid (0.440 g; 74% yield). ¹H NMR (400 MHz, CDCl₃): δ 6.86 (s, 6H, ArH), 4.10-4.00 (t, 6 H, 3J=6.6 Hz, CH₂C(O)OCH₂ (CH₂)₁₄CH₃),3.87-3.69 (dd, 6 H, 3J=13.7 Hz, 3J (CNH)=42.4 Hz CH₂—CH—N), 3.43 (s, 6H, CH₂C(O)OCH₂ (CH₂)₁₄CH₃), 2.40-2.28 (m, 6 H, aliphatic), 2.15-1.95 (m,6 H, aliphatic), 1.75-1.60 (m, 6 H, aliphatic), 1.60-1.55 (m, 6 H,aliphatic) 1.37-1.05 (m, 84 H, aliphatic) 0.92-0.86 (t, 9 H, 3J=6.8 Hz.ESIMS (+) Calcd for C₉₆H₁₆₃N₆O₉: 1544; Found: 1545 [M+H]⁺.

Example 76

[0560]

[0561] Hexamer 1A-Me. A solution of2-hydroxy-5-methyl-1,3-benzenedicarboxaldehye (53 mg, 0.32 mmol) indichloromethane (0.6 mL) was added to a solution of(1,2R)-(−)-1,2-diaminocyclohexane (37 mg, 0.32 mmol) in dichloromethane(0.5 mL). The mixture was stirred at ambient temperature for 16 h, addeddropwise to methanol (75 mL) and chilled (4° C.) for 4 h. Theprecipitate was collected to afford 71 mg (92%) of hexamer 1A-Me. ¹H NMR(CDCl₃): δ 13.88 (s, 3H, OH), 8.66 (s, 3H, ArCH═N), 8.19 (s, 3H,ArCH═N), 7.52 (d, 3H, J=2 Hz, Ar H), 6.86 (d, 3H, J=2 Hz, Ar H), 3.35(m, 6H, cyclohexane 1,2-H's), 2.03 (3, 9H, Me), 1.6-1.9 (m, 18H,cyclohexane 3,6-H₂ and 4eq,5eq-H's), 1.45 (m, 6H, cyclohexane4ax,5ax-H's); 13C NMR δ 63.67, 159.55, 156.38, 134.42, 129.75, 127.13,119.00, 75.68, 73.62, 33.68, 33.41, 24.65, 24.57, 20.22; ESI(+) MS m/e(%) 727 M+H (100); IR 1634 cm⁻.

Example 77

[0562]

[0563] 32.7 mg Hexamer 1jh (recrystallized times) was added to 30 mL dryTHF. 100 μL triethylamine and 100 μL acryloyl chloride (freshlydistilled) were added subsequently to the THF mixture using Schlenktechnique. Solution was stirred for 18 hrs in an acetone/dry ice bath.After removal of solvent a white precipitate remained. The precipitatewas redissolved in CH₂Cl₂ and filtered through a fritted funnel. CH₂Cl₂solution was added to the separatory funnel and washed one time withwater followed by two brine (NaCl) washes. The CH₂Cl₂ solution was driedover MgSO₄ and then filtered to remove MgSO₄. A yellow precipitateremained after solvent removal. ¹H NMR (CDCl₃): δ −0.867-0.990 (3 H),1.259 (21.8 H), 1.39 (1.86 H), 1.64 (12.7 H), 2.8 (1.25 H), 3.46-3.62(2.47 H), 3.71 (0.89 H), 3.99 (2.46 H), 5.06 (0.71 H), 5.31 (3.80 H),5.71 (1.43 H), 5.90 (0.78 H), 6.2-6.4 (2.49 H), 6.59 (0.80 H), 6.78(0.47 H), 6.98 (0.28 H). FTIR-ATR: 3340, 2926 (—CH₂—), 2854 (—CH₂—),1738 (Ester Carbonyl), 1649 and 1613 (Acrylate), 983 (═CH), 959 sh(═CH₂). ESI-MS: 1978.5 (Hex1JhAC+8-AC), 1948.8 (Hex1JhAC+7-AC+Na+),1923.3 (Hex1JhAC+7AC), 1867.6 (Hex1JhAC+6-AC), 1842.6, 1759.7(Hex1JhAC+4-AC).

Example 78

[0564] The Langmuir isotherm and isobaric creep for hexamer 1a-Me areshown in FIGS. 20A and 20B, respectively.

[0565] The relative stability of the Langmuir film of Hexamer 1a-Me isillustrated by the isobaric creep data shown in FIG. 20B. The area ofthe film decreased by about 30% after about 30 min at 5 mN/m surfacepressure. The Langmuir isotherm and isobaric creep for Hexamer 1a-C15are shown in FIGS. 21A and 21B, respectively. The relative stability ofthe Langmuir film of Hexamer 1a-C15 is illustrated by the isobaric creepdata shown in FIG. 21B. The area of the film decreased by about 1-2%after about 30 min at 10 mN/m surface pressure, and by about 2% afterabout 60 min. The collapse pressure was about 18 mN/m for Hexamer1a-C15.

What is claimed is:
 1. A nanofilm composition comprising a reactionproduct of macrocyclic modules and at least one polymeric component. 2.The nanofilm composition of claim 1, wherein the macrocyclic modules arecoupled to each other.
 3. The nanofilm composition of claim 2, whereinthe macrocyclic modules are coupled to each other through linkermolecules.
 4. The nanofilm composition of claim 3, wherein the linkermolecules are selected from the group consisting of

and mixtures therefor; wherein m is 1-10, n is 1-6, R is —H or —CH₃, R′is —(CH₂)_(n)— or phenyl, R″ is —(CH₂)_(n)—, polyenthylene glycol (PEG),or polypropylene glycol (PPG), and X is Br, Cl, I, or other leavinggroup.
 5. The nanofilm composition of claim 1, wherein the macrocyclicmodules are coupled to the at least one polymeric component.
 6. Thenanofilm composition of claim 5, wherein the macrocyclic modules arecoupled to the at least one polymeric component through linkermolecules.
 7. The nanofilm composition of claim 6, wherein the linkermolecules are selected from the group consisting of

and mixtures thereof; wherein m is 1-10, n is 1-6, R is —H or —CH₃, R′is —(CH₂)_(n)— or phenyl, R″ is —(CH₂)_(n)—, polyethylene glycol (PEG),or polypropylene glycol (PPG), and X is Br, Cl, I, or other leavinggroup.
 8. The nanofilm composition of claim 1, wherein the macrocyclicmodules are selected from the group consisting of Hexamer 1a, Hexamer1dh, Hexamer 3j-amine, Hexamer 1jh, Hexamer 1jh-AC, Hexamer2j-amine/ester, Hexamer 1dh-acryl, Octamer 5jh-aspartic, Octamer4jh-acryl, and mixtures thereof.
 9. The nanofilm composition of claim 8,wherein the macrocyclic modules are Hexamer 1dh.
 10. The nanofilmcomposition of claim 1, wherein the polymeric component is selected fromthe group consisting of poly(maleic anhydride)s, poly(ethylene-co-maleicanhydride)s, poly(maleic anhydride-co-alpha olefin)s, polyacrylates,polymethylmethacrylate, polymers containing at least one oxacyclopropanegroup, polyethyleneimides, polyetherimides, polyethylene oxides,polypropylene oxides, polyurethanes, polystyrenes, poly(vinyl acetate)s,polytetrafluoroethylenes, polyethylenes,kpolypropylenes,ethylene-propylene copolymers, polyisoprenes, polyneopropenes,polyamides, polyimides, polysulfones, polyethersulfones, polyethyleneterephthalates, polybutylene terephthalates, polysulfonamides,polysulfoxides, polyglycolic acids, polyacrylamides, polyvinylalcohols,polyesters, polyester ionomers, polycarbonates, polyvinylchlorides,polyvinylidene chlorides, polyvinylidene fluorides,polyvinylpyrrolidones, polylactic acids, polypeptides, polysorbates,polylysines, hydrogels, carbohydrates, polysaccharides, agaroses,amyloses, amylopectins, glycogens, dextrans, celluloses, celluloseacetates, chitins, chitosans, peptidoglycans, glycosaminoglycans,polynucleotides, poly(T), poly(A), nucleic acids, proteoglycans,glycoproteins, glycolipids, and mixtures thereof.
 11. The nanofilmcomposition of claim 1, wherein the polymeric component is poly(maleicanhydride-co-alpha olefin).
 12. The nanofilm composition of claim 1,wherein the polymeric component comprises a polymerizable monomer. 13.The nanofilm composition of claim 12, wherein the polymerizable monomercomprises CH₂═CHC(O)OCH₂CH₂OH.
 14. The nanofilm composition of claim 1,wherein the polymeric component comprises a polymerizable amphiphile.15. The nanofilm composition of claim 13, wherein the polymerizableamphiphile is selected from the group consisting of amphiphilicacrylates, amphiphilic acrylamides, amphiphilic vinyl esters,amphiphilic anilines, amphiphilic diynes, amphiphilic dienes,amphiphilic acrylic acids, amphiphilic enes, amphiphilic cinnamic acids,amphiphilic amino-esters, amphiphilic oxiranes, amphiphilic amines,amphiphilic diesters, amphiphilic diacids, amphiphilic diols,amphiphilic polyols, and amphiphilic diepoxides.
 16. The nanofilm ofclaim 1, further comprising a non-polymerizable amphiphile.
 17. Thenanofilm of claim 16, wherein the non-polymerizable amphiphile isselected from the group consisting of decylamine and stearic acid. 18.The nanofilm composition of claim 1 prepared by spin coating, spraycoating, dip coating, grafting, casting, phase inversion,electroplating, or knife-edge coating.
 19. The nanofilm composition ofclaim 1, wherein the area fraction of the polymeric components is from0.5 to 98 percent.
 20. The nanofilm composition of claim 1, wherein thearea fraction of the polymeric components is less than about 20 percent.21. The nanofilm composition of claim 1, wherein the area fraction ofthe polymeric components is less than about 5 percent.
 22. The nanofilmcomposition of claim 1, wherein the thickness of the nanofilmcomposition is less than about 30 nanometers.
 23. The nanofilmcomposition of claim 1, wherein the thickness of the nanofilmcomposition is less than about 6 nanometers.
 24. The nanofilmcomposition of claim 1, wherein the thickness of the nanofilmcomposition is less than about 2 nanometers.
 25. The nanofilmcomposition of claim 1, wherein the surface loss modulus of the nanofilmcomposition at a surface pressure from 5-30 mN/m is less than about 50%of the surface loss modulus of the same nanofilm composition madewithout the polymeric components.
 26. The nanofilm composition of claim1, wherein the surface loss modulus of the nanofilm composition at asurface pressure from 5-30 mN/m is less than about 30% of the surfaceloss modulus of the same nanofilm composition made without the polymericcomponents.
 27. The nanofilm composition of claim 1, wherein the surfaceloss modulus of the nanofilm composition at a surface pressure from 5-30mN/m is less than about 20% of the surface loss modulus of the samenanofilm composition made without the polymeric components.
 28. Thenanofilm composition of claim 1, having the following filtrationfunction: MOLECULAR SOLUTE WEIGHT PASS/NO PASS Albumin 68 kDa NPOvalbumin 44 kDa P Myoglobin 17 kDa P β₂-Microglobulin 12 kDa P Insulin5.2 kDa P Vitamin B₁₂ 1350 Da P Urea, H₂O, ions <1000 Da P


29. The nanofilm composition of claim 1, having the following filtrationfunction: MOLECULAR SOLUTE WEIGHT PASS/NO PASS β₂-Microglobulin 12 kDaNP Insulin 5.2 kDa NP Vitamin B₁₂ 1350 Da NP Glucose 180 Da NPCreatinine 131 Da NP H₂PO₄ ⁻, HPO₄ ²⁻ ≈97 Da NP HCO₃ ⁻ 61 Da NP Urea 60Da NP K+ 39 Da P Na+ 23 Da P


30. The nanofilm composition of claim 1, wherein the nanofilm isimpermeable to viruses and larger species.
 31. The nanofilm compositionof claim 1, wherein the nanofilm is impermeable to immunoglobulin G andlarger species.
 32. The nanofilm composition of claim 1, wherein thenanofilm is impermeable to albumin and larger species.
 33. The nanofilmcomposition of claim 1, wherein the nanofilm is impermeable toβ₂-Microglobulin and larger species.
 34. The nanofilm composition ofclaim 1, wherein the nanofilm is permeable only to water and smallerspecies.
 35. The nanofilm composition of claim 1, having a molecularweight cut-off of 13 kDa.
 36. The nanofilm composition of claim 1,having a molecular weight cut-off of 190 Da.
 37. The nanofilmcomposition of claim 1, having a molecular weight cut-off of 100 Da. 38.The nanofilm composition of claim 1, having a molecular weight cut-offof 45 Da.
 39. The nanofilm composition of claim 1, having a molecularweight cut-off of 20 Da.
 40. The nanofilm composition of claim 1, havinghigh permeability for water molecules and Na⁺, K⁺, and Cs⁺ in water. 41.The nanofilm composition of claim 36, having low permeability forglucose and urea.
 42. The nanofilm composition of claim 1, having highpermeability for water molecules and Cl⁻ in water.
 43. The nanofilmcomposition of claim 1, having high permeability for water molecules andK⁺ in water, and low permeability for Na⁺ in water.
 44. The nanofilmcomposition of claim 1, having high permeability for water molecules andNa⁺ in water, and low permeability for K⁺ in water.
 45. The nanofilmcomposition of claim 1, having low permeability for urea, creatinine,Li⁺, Ca² ⁺, and Mg² ⁺ in water.
 46. The nanofilm composition of claim41, having high permeability for Na⁺, K⁺, hydrogen phosphate, anddihydrogen phosphate in water.
 47. The nanofilm composition of claim 41,having high permeability for Na⁺, K⁺, and glucose in water.
 48. Thenanofilm composition of claim 1, having low permeability for myoglobin,ovalbumin, and albumin in water.
 49. The nanofilm composition of claim1, having high permeability for organic compounds and low permeabilityfor water.
 50. The nanofilm composition of claim 1, having lowpermeability for organic compounds and high permeability for water. 51.The nanofilm composition of claim 1, having low permeability for watermolecules and high permeability for helium and hydrogen gases.
 52. Ananofilm composition comprising at least two layers of the nanofilm ofclaim
 1. 53. The nanofilm composition of claim 52, fuirther comprisingat least one spacing layer between any two of the nanofilm layers. 54.The nanofilm composition of claim 53, wherein the spacing layercomprises a layer of a polymer, a gel, or inorganic particles.
 55. Thenanofilm composition of claim 1, deposited on a substrate.
 56. Thenanofilm composition of claim 55, wherein the nanofilm is coupled to thesubstrate through the polymeric component.
 57. The nanofilm compositionof claim 55, wherein the substrate is porous.
 58. The nanofilmcomposition of claim 55, wherein the substrate is non-porous.
 59. Thenanofilm composition of claim 55, wherein the nanofilm is coupled to thesubstrate through biotin-strepavidin mediated interaction.
 60. Ananofilm composition comprising a reaction product of a polymericcomponent and an amphiphile.
 61. The nanofilm of claim 60, wherein theamphiphile is a polymerizable amphiphile.
 62. The nanofilm compositionof claim 61, wherein the polymerizable amphiphile is selected from thegroup consisting of amphiphilic acrylates, amphiphilic acrylamides,amphiphilic vinyl esters, amphiphilic anilines, amphiphilic diynes,amphiphilic dienes, amphiphilic acrylic acids, amphiphilic enes,amphiphilic cinnamic acids, amphiphilic amino-esters, amphiphilicoxiranes, amphiphilic amines, amphiphilic diesters, amphiphilic diacids,amphiphilic diols, amphiphilic polyols, and amphiphilic diepoxides. 63.The nanofilm of claim 60, wherein the amphiphile is non-polymerizable.64. The nanofilm of claim 63, wherein the non-polymerizable amphiphileis selected from the group consisting of decylamine and stearic acid.65. The nanofilm composition of claim 60, wherein the polymericcomponent is selected from the group consisting of poly(maleicanhydride)s, poly(ethylene-co-maleic anhydride)s, poly(maleicanhydride-co-alpha olefin)s, polyacrylates, polymethylmethacrylate,polymers containing at least one oxacyclopropane group,polyethyleneimides, polyetherimides, polyethylene oxides, polypropyleneoxides, polyurethanes, polystyrenes, poly(vinyl acetate)s,polytetrafluoroethylenes, polyethylenes, polypropylenes,ethylene-propylene copolymers, polyisoprenes, polyneopropenes,polyamides, polyimides, polysulfones, polyethersulfones, polyethyleneterephthalates, polybutylene terephthalates, polysulfonamides,polysulfoxides, polyglycolic acids, polyacrylamides, polyvinylalcohols,polyesters, polyester ionomers, polycarbonates, polyvinylchlorides,polyvinylidene chlorides, polyvinylidene fluorides,polyvinylpyrrolidones, polylactic acids, polypeptides, polysorbates,polylysines, hydrogels, carbohydrates, polysaccharides, agaroses,amyloses, amylopectins, glycogens, dextrans, celluloses, celluloseacetates, chitins, chitosans, peptidoglycans, glycosaminoglycans,polynucleotides, poly(T), poly(A), nucleic acids, proteoglycans,glycoproteins, glycolipids, and mixtures thereof.
 66. The nanofilm ofclaim 60, wherein the polymeric component is amphiphilic.
 67. Thenanofilm of claim 60, wherein the polymeric component comprises apolymerizable monomer.
 68. The nanofilm of claim 60, wherein thepolymeric component comprises a polymerizable amphiphile.
 69. Thenanofilm composition of claim 61, wherein the nanofilm is prepared by aprocess comprising polymerizing the polymerizable amphiphiles at anair-water interface.
 70. The nanofilm composition of claim 60, whereinthe nanofilm is prepared by a process comprising polymerizing thepolymeric component at an air-water interface.
 71. The nanofilm of claim63, wherein the polymeric component is a polymer, and wherein thenon-polymerizable amphiphiles are coupled to the polymer.
 72. A nanofilmcomposition comprising a reaction product of a polymeric component,wherein the polymeric components are linked by linker molecules.
 73. Thenanofilm composition of claim 72, wherein the polymeric component isselected from the group consisting of poly(maleic anhydride)s,poly(ethylene-co-maleic anhydride)s, poly(maleic anhydride-co-alphaolefin)s, polyacrylates, polymethylmethacrylate, polymers containing atleast one oxacyclopropane group, polyethyleneimides, polyetherimides,polyethylene oxides, polypropylene oxides, polyurethanes, polystyrenes,poly(vinyl acetate)s, polytetrafluoroethylenes, polyethylenes,polypropylenes, ethylene-propylene copolymers, polyisoprenes,polyneopropenes, polyarnides, polyimides, polysulfones,polyethersulfones, polyethylene terephthalates, polybutyleneterephthalates, polysulfonamides, polysulfoxides, polyglycolic acids,polyacrylamides, polyvinylalcohols, polyesters, polyester ionomers,polycarbonates, polyvinylchlorides, polyvinylidene chlorides,polyvinylidene fluorides, polyvinylpyrrolidones, polylactic acids,polypeptides, polysorbates, polylysines, hydrogels, carbohydrates,polysaccharides, agaroses, amyloses, amylopectins, glycogens, dextrans,celluloses, cellulose acetates, chitins, chitosans, peptidoglycans,glycosaminoglycans, polynucleotides, poly(T), poly(A), nucleic acids,proteoglycans, glycoproteins, glycolipids, and mixtures thereof.
 74. Ananofilm composition comprising a reaction product of at least twopolymeric components, wherein the first polymeric component is apolymerizable amphiphile, and the second polymeric component is apolymerizable monomer.
 75. A composition comprising a mixture ofmacrocyclic modules and at least one polymeric component in organicsolvent.
 76. A composition comprising a thin film of a reaction productof macrocyclic modules and at least one polymeric component, wherein thecomposition is prepared by a process comprising contacting themacrocyclic modules and the at least one polymeric component at anair-liquid or liquid-liquid interface.
 77. A method for making ananofilm composition comprising: (a) providing a mixture of macrocyclicmodules and at least one polymeric component; and (b) forming themixture into a thin film at an air-liquid or liquid-liquid interface.78. The method of claim 77, wherein the polymeric component ispolymerizable, further comprising polymerizing the polymeric componentat the air-liquid or liquid-liquid interface.
 79. A method for making ananofilm composition comprising the reaction product of macrocyclicmodules and at least one polymeric component, comprising: (a) providinga subphase containing the at least one polymeric component; and (b)contacting macrocyclic modules with the surface of the subphase.
 80. Themethod of claim 79, further comprising: (c) contacting a linker moleculewith the surface of the subphase.
 81. A method for making a nanofilmcomposition comprising the reaction product of macrocyclic modules andat least one polymeric component, comprising: (a) providing a firstliquid phase comprising the macrocyclic modules; (b) providing a secondliquid phase comprising the at least one polymeric component; and (c)forming a liquid-liquid interface from the first liquid phase and thesecond liquid phase.
 82. A method for filtration comprising using thenanofilm composition of claim 1 to separate a component from a fluid.83. A method for filtration comprising using the nanofilm composition ofclaim 1 to separate a component from a mixture of at least two gases.